Pyrrolidine modulators of chemokine receptor activity

ABSTRACT

The present invention is directed to pyrrolidine compounds of the formula I:                    
     (wherein R 1 , R 2 , R 3 , R 4c , R 4d , and R 4f  are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. 119(e) from ProvisionalApplication No. 60/122,577, filed Mar. 2, 1999.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3,165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). There aretwo classes of chemokines, C-X-C (α) and C-C (β), depending on whetherthe first two cysteines are separated by a single amino acid (C-X-C) orare adjacent (C-C). The α-chemokines, such as interleukin-8 (IL-8),neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatoryactivity protein (MGSA) are chemotactic primarily for neutrophils,whereas β-chemokines, such as RANTES, MIP-1α, MIP-1β, monocytechemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotacticfor macrophages, T-cells, eosinophils and basophils (Deng, et al.,Nature, 381, 661-666 (1996)).

The chemokines bind specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G protein, resulting in a rapid increase inintracellular calcium concentration. There are at least seven humanchemokine receptors that bind or respond to β-chemokines with thefollowing characteristic pattern: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MIP-1β, MCP-3, RANTES] (Ben-Barruch, et al., J. Biol. Chem.,270, 22123-22128 (1995); Beote, et al, Cell, 72, 415-425 (1993)); CCR-2Aand CCR-2B (or “CKR-2A”/“CKR-2A” or “CC-CKR-2A”/“CC-CKR-2A”) [MCP-1,MCP-3, MCP4]; CCR-3 (or “CKR-3” or “CC-CKR-3”) [eotaxin, RANTES, MCP-3](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995); CCR-4 (or“CKR4” or “CC-CKR4”) [MIP-1α, RANTES, MCP-1] (Power, et al., J. Biol.Chem., 270, 19495-19500 (1995)); CCR-5 (or “CKR-5” or “CC-CKR-5”)[MIP-1α:, RANTES, MIP-1β] (Sanson, et al., Biochemistry, 35, 3362-3367(1996)); and the Duffy blood-group antigen [RANTES, MCP-1] (Chaudhun, etal., J. Biol. Chem., 269, 7835-7838 (1994)). The β-chemokines includeeotaxin, MIP (“macrophage inflammatory protein”), MCP (“monocytechemoattractant protein”) and RANTES (“regulation-upon-activation,normal T expressed and secreted”).

Chemokine receptors, such as CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4,CCR-5, CXCR-3, CXCR-4, have been implicated as being important mediatorsof inflammatory and immunoregulatory disorders and diseases, includingasthma, rhinitis and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. A reviewof the role of chemokines in allergic inflammation is provided by Kita,H., et al., J. Exp. Med. 183, 2421-2426 (1996). An antagonist of theCCR3 receptor, Met-chemokine beta 7, has been proposed to be useful inameliorating leukocyte infiltration associated with allergicinflammation (Nibbs, et al., J. Immunol., 164, 1488-1497 (2000)).Accordingly, agents which modulate chemokine receptors would be usefulin such disorders and diseases. Compounds which modulate chemokinereceptors would be especially useful in the treatment and prevention ofatopic conditions including allergic rhinitis, dermatitis,conjunctivitis, and particularly bronchial asthma.

A retrovirus designated human immunodeficiency virus (HIV-1) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV.

Certain compounds have been demonstrated to inhibit the replication ofHIV, including soluble CD4 protein and synthetic derivatives (Smith, etal., Science, 238, 1704-1707 (1987)), dextran sulfate, the dyes DirectYellow 50, Evans Blue, and certain azo dyes (U.S. Pat. No. 5,468,469).Some of these antiviral agents have been shown to act by blocking thebinding of gp120, the coat protein of HIV, to its target, the CD4glycoprotein of the cell.

Entry of HIV-1 into a target cell requires cell-surface CD4 andadditional host cell cofactors. Fusin has been identified as a cofactorrequired for infection with virus adapted for growth in transformedT-cells, however, fusin does not promote entry of macrophagetropicviruses which are believed to be the key pathogenic strains of HIV invivo. It has recently been recognized that for efficient entry intotarget cells, human immunodeficiency viruses require the chemokinereceptors CCR-5 and CXCR-4, as well as the primary receptor CD4 (Levy,N. Engl. J. Med., 335(20), 1528-1530 (Nov. 14, 1996). The principalcofactor for entry mediated by the envelope glycoproteins of primarymacrophage-trophic strains of HIV-1 is CCR5, a receptor for theβ-chemokines RANTES, MIP-1α and MIP-1β (Deng, et al., Nature, 381,661-666 (1996)). HIV attaches to the CD4 molecule on cells through aregion of its envelope protein, gp120. It is believed that the CD-4binding site on the gp120 of HIV interacts with the CD4 molecule on thecell surface, and undergoes conformational changes which allow it tobind to another cell-surface receptor, such as CCR5 and/or CXCR-4. Thisbrings the viral envelope closer to the cell surface and allowsinteraction between gp41 on the viral envelope and a fusion domain onthe cell surface, fusion with the cell membrane, and entry of the viralcore into the cell. It has been shown that β-chemokine ligands preventHIV-1 from fusing with the cell (Dragic, et al., Nature, 381, 667-673(1996)). It has further been demonstrated that a complex of gp120 andsoluble CD4 interacts specifically with CCR-5 and inhibits the bindingof the natural CCR-5 ligands MIP-1α and MIP-1β(Wu, et al., Nature, 384,179-183 (1996); Trkola, et al., Nature, 384, 184-187 (1996)).

Humans who are homozygous for mutant CCR-5 receptors which do not serveas co-receptors for HIV-1 in vitro appear to be unusually resistant toHIV-1 infection and are not immuno-compromised by the presence of thisgenetic variant (Nature, 382, 722-725 (1996)). Absence of CCR-5 appearsto confer protection from HIV-1 infection (Nature, 382, 668-669 (1996)).Other chemokine receptors may be used by some strains of HIV-1 or may befavored by non-sexual routes of transmission. Although most HIV-1isolates studied to date utilize CCR-5 or fusin, some can use both aswell as the related CCR-2B and CCR-3 as co-receptors (Nature Medicine,2(11), 1240-1243 (1996)). Nevertheless, drugs targeting chemokinereceptors may not be unduly compromised by the genetic diversity ofHIV-1 (Zhang, et al., Nature, 383, 768 (1996)). Accordingly, an agentwhich could block chemokine receptors in humans who possess normalchemokine receptors should prevent infection in healthy individuals andslow or halt viral progression in infected patients. By focusing on thehost's cellular immune response to HIV infection, better therapiestowards all subtypes of HWV may be provided. These results indicate thatinhibition of chemokine receptors presents a viable method for theprevention or treatment of infection by HIV and the prevention ortreatment of AIDS.

The peptides eotaxin, RANTES, MIP-1α, MIP-1β, MCP-1, and MCP-3 are knownto bind to chemokine receptors. As noted above, the inhibitors of HIV-1replication present in supernatants of CD8+T cells have beencharacterized as the β-chemokines RANTES, MIP-1α and MIP-1β.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are modulators ofchemokine receptor activity and are useful in the prevention ortreatment of certain inflammatory and immunoregulatory disorders anddiseases, allergic diseases, atopic conditions including allergicrhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Theinvention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which chemokine receptorsare involved.

The present invention is further concerned with compounds which inhibitthe entry of human immunodeficiency virus (HIV) into target cells andare of value in the prevention of infection by HIV, the treatment ofinfection by HIV and the prevention and/or treatment of the resultingacquired immune deficiency syndrome (AIDS). The present invention alsorelates to pharmaceutical compositions containing the compounds and to amethod of use of the present compounds and other agents for theprevention and treatment of AIDS and viral infection by HIV.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula I:

wherein:

R¹ is —X-R⁸, wherein X is selected from the group consisting of:

(1) —CH₂—,

(2) —CO—,

(3) —CH₂CH₂—,

(4) —CH₂CH₂CH₂—, and

(5) —CH(C₁₋₆ alkyl)—,

and wherein R⁸ is a selected from:

phenyl, naphthyl, biphenyl, fluorenyl, indenyl, indanyl,dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, adamantyl, andheterocycle, which may be unsubstituted or substituted, where thesubstituents are independently selected from:

(a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(A) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(B) naphthyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(C) heterocycle,unsubstituted or substituted, wherein the substituentsare independently selected from: halogen, hydroxy, C₁₋₆ alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C1-6 alkyl), or trifluoromethyl,

(D) hydroxy,

(E) —O(C₁₋₆ alkyl),

(F) —CO₂(C₁₋₆ alkyl),

(G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is an integer selected from 0, 1and 2,

(H) halogen,

(I) —NH₂,

(J) —NH(C₁₋₆ alkyl), and

(K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl),

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0,1 and 2,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvi) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —O₂CO-R⁹, and

(xxx) —CO-R⁹,

(b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰,

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvii) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(c) —NO₂,

(d) hydroxy,

(e) halogen,

(f) —NR⁹R¹⁰,

(g) —NR⁹-COR¹⁰,

(h) —NR⁹-CO₂R¹⁰,

(i) —CO—NR⁹R¹⁰,

(j) —OCO—NR⁹R¹⁰,

(k) —NR⁹CO—NR⁹R¹⁰,

(l) —S(O)₂—NR⁹R¹⁰,

(m) —NR⁹S(O)₂-R¹⁰,

(n) —NR⁹S(O)₂—NR⁹R¹⁰,

(o) —S(O)_(n)-R⁹,

(p) —CF₃,

(q) —CHF₂,

(r) —CH₂F,

(s) —OCO-R⁹,

(t) —OCO₂-R⁹, and

(u) —CO-R⁹;

R² is selected from the group consisting of:

wherein R⁵ is a selected from:

(1) —NR⁶CO—O-R⁷, wherein R⁶ is hydrogen, C₁₋₆ alkyl or C-₁₋₆ alkyl-C₅₋₆cycloalkyl, and R⁷ is C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,wherein the alkyl, cycloalkyl, benzyl or phenyl is unsubstituted orsubstituted with halogen C₁₋₃alkyl, C₁₋₃alkoxy or trifluoromethyl,

(2) phenyl, which is unsubstituted or substituted with halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, ortrifluoromethyl,

(3) -pyridyl,

(4) -thienyl,

(5) -C₁₋₆alkyl-phenyl, -C₁₋₆alkyl-naphthyl, -C₁₋₆alkyl-indenyl,-C₁₋₆alkyl-indanyl, and -C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl; and wherein the-C₁₋₆alkyl is optionally substituted with oxo, hydroxy, C₁₋₆alkoxy,acetoxy, or halogen,

(6) —O-C₁₋₆alkyl-phenyl, —O-C₁₋₆alkyl-naphthyl, —O-C₁₋₆alkyl-indenyl,—O-C₁₋₆alkyl-indanyl, and —O-C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl,

(7) -C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl, and

(8) -C₁₋₄alkyl-S(O)_(n)C₁₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl;

and wherein R¹¹ is a selected from:

(1) -hydrogen,

(2) —OH,

(3) -C₁₋₆alkyl, and

(4) -halogen;

R³ is selected from the group consisting of:

(1) —CHO,

(2) —CO₂(C₁₋₆ alkyl),

(3) —CO-R⁹,

(4) —CONR⁹R¹⁰,

(5) —CONR⁹-COR¹⁰,

(6) —CONR⁹-CO₂R¹⁰,

(7) —C(R⁹)(OR⁹)(OR¹⁰),

(8) —C(R⁹)(SR⁹(SR¹⁰),

(9) —(R⁹)(OR¹⁴)(OR¹⁵), wherein R¹⁴ and R¹⁵ are joined together in a C₂₋₃alkyl group to form a 5- or 6-membered ring which is substituted withR¹² and R¹³ wherein:

R¹² and R¹³ are independently selected from:

(a) hydrogen,

(b) —CO₂(C₁₋₆alkyl),

(c) hydrogen,

(d) halogen,

(e) —NR⁹R¹⁰,

(f) —NR⁹-COR¹⁰,

(g) —NR⁹-CO₂R¹⁰,

(h) —CF₃,

(i) —CHF₂,

(j) —CH₂F,

(k) —O-R⁹,

(l) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) —CO₂(CO₁₋₆ alkyl),

(ii) hydroxy,

(iii) halogen,

(iv) —NR⁹R¹⁰,

(v) —NR⁹-COR¹⁰,

(vi) —NR⁹-CO₂R¹⁰,

(vii) phenyl,

(viii) —CF₃,

(ix) —CHF₂,

(x) —CH₂F, and

(xi) —O-R⁹,

(m) phenyl or heterocycle, wherein the phenyl or heterocycle isunsubstituted or substituted, wherein the substituents are independentlyselected from:

(i) —CO₂(C₁₋₆ alkyl),

(ii) hydrogen,

(iii) halogen,

(iv) —NR⁹R¹⁰,

(v) —NR⁹-COR¹⁰,

(vi) —NR⁹-CO₂R¹⁰,

(vii) phenyl,

(viii) —CF₃,

(ix) —CHF₂,

(x) —CH₂F, and

(xi) —O-R⁹,

(10) —C(R⁹)(SR¹⁴)(SR¹⁵),

(11) -cyclopentyl, which is substituted with R¹² and R¹³,

(12) -cyclohexyl, which is substituted with R¹² and R¹³,

(13) -tetrahydrofuranyl, which is substituted with R¹² and R¹³,

(14) -tetrahydropyranyl, which is substituted with R¹² and R¹³,

R^(4c), R^(4d), and R^(4f) are independently selected from the groupconsisting of:

(1) hydrogen, and

(2) C₁₋₆ alkyl;

and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

Preferred compounds of the present invention include those of formulaIa:

wherein:

R¹, R² and R³ are defined herein; and pharmaceutically acceptable saltsand individual diastereomers thereof.

Preferred compounds of the present invention include those of theformula Ib:

wherein:

R¹ is —X-R⁸, wherein X is selected from the group consisting of:

(1) —CH₂—,

(2) —CO—, and

(3) —CH₂CH₂—,

and wherein R⁸ is a selected from:

phenyl, naphthyl, biphenyl, fluorenyl, indenyl, indanyl,dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, adamantyl, andheterocycle, which may be unsubstituted or substituted, where thesubstituents are independently selected from:

(a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(A) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(B) naphthyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(C) heterocycle,unsubstituted or substituted, wherein the substituentsare independently selected from: halogen, hydroxy, C-₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆alkyl), or trifluoromethyl,

(D) hydroxy,

(E) —O(C₁₋₆ alkyl),

(F) —CO₂(C₁₋₆ alkyl),

(G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is an integer selected from 0, 1and 2,

(H) halogen,

(I) —NH₂,

(J) —NH(C₁₋₆ alkyl), and

(K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl),

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0, 1 and2,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvi) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —-CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰,

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvii) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(c) —NO₂,

(d) hydroxy,

(e) halogen,

(f) —NR⁹R¹⁰,

(g) —NR⁹-COR¹⁰,

(h) —NR⁹-CO₂R¹⁰,

(i) —CO—NR⁹R¹⁰,

(j) —OCO—NR⁹R¹⁰,

(k) —NR⁹CO—NR⁹R¹⁰,

(l) —S(O)₂—NR⁹R¹⁰,

(m) —NR⁹S(O)₂-R¹⁰,

(n) —NR⁹S(O)₂—NR⁹R¹⁰,

(o) —S(O)_(n)-R⁹,

(p) —CF₃,

(q) —CHF₂,

(r) —CH₂F,

(s) —OCO-R⁹,

(t) —OCO₂-R⁹, and

(u) —CO-R⁹;

R² is:

wherein R⁵ is a selected from;

(1) —NR⁶CO—O-R⁷, wherein R⁶ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkyl-C₅₋₆cycloalkyl, and R⁷ is C₁₋₆ alkyl, C₅₋₆ cycloalkyl, benzyl or phenyl,wherein the alkyl, cycloalkyl, benzyl or phenyl is unsubstituted orsubstituted with halogen, C₁₋₃alkyl, C₁₋₃alkoxy or trifluoromethyl,

(2) phenyl, which is unsubstituted or substituted with halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, ortrifluoromethyl,

(3) -pyridyl,

(4) -thienyl,

(5) -C₁₋₆alkyl-phenyl, -C₁₋₆alkyl-naphthyl, -C₁₋₆alkyl-indenyl,-C₁₋₆alkyl-indanyl, and -C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl; and wherein the-C₁₋₆alkyl is optionally substituted with oxo, hydroxy, C₁₋₆alkoxy,acetoxy, or halogen,

(6) —O-C₁₋₆alkyl-phenyl, —O-C₁₋₆alkyl-naphthyl, —O-C₁₋₆alkyl-indenyl,—O-C₁₋₆alkyl-indanyl, and —O-C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl,

(7) -C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, NHR⁹, —NR⁹R¹⁰, or trifluoromethyl, and

(8) -C₁₋₄alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl;

and wherein R¹¹ is a selected from:

(1) -hydrogen,

(2) —OH,

(3) -C₁₋₆alkyl, and

(4) -halogen;

R¹² and R¹³ are independently selected from:

(1) hydrogen,

(2) —CO₂(C₁₋₆ alkyl),

(3) hydroxy,

(4) halogen,

(5) —NR⁹R¹⁰,

(6) —NR⁹-COR¹⁰,

(7) —NR⁹-CO₂R¹⁰,

(8) —CF₃,

(9) —CHF₂,

(10) —CH₂F,

(11) —O-R⁹,

(12) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(a) —CO₂(C₁₋₆ alkyl),

(b) hydroxy,

(c) halogen,

(d) —NR⁹R¹⁰,

(e) —NR⁹-COR¹⁰,

(f) —NR⁹-CO₂R¹⁰,

(g) phenyl,

(h) —CF₃,

(i) —CHF₂,

(j) —CH₂F, and

(k) —O-R⁹,

(14) phenyl or heterocycle, wherein the phenyl or heterocycle isunsubstituted or substituted, wherein the substituents are independentlyselected from:

(a) —CO₂(C₁₋₆ alkyl),

(b) hydroxy,

(c) halogen,

(d) —NR⁹R¹⁰,

(e) —NR⁹-CO₂R¹⁰,

(f) —NR⁹-CO₂R¹⁰,

(g) phenyl,

(h) —CF₃,

(i) —CHF₂,

(j) —CH₂F, and

(k) —O-R⁹,

Y and Z are independently selected from: C₁ alkyl, —O—, —S(O)_(n)— and—N(R⁹)—;

m is an integer selected from 1 and 2;

and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

More preferred compounds of the present invention include those of theformula Ic:

wherein:

R¹, R⁵, R¹², R¹³, Y, Z and m are defined herein; and pharmaceuticallyacceptable salts and individual diastereomers thereof.

Highly preferred compounds of the present invention further includethose of the formula Id:

wherein:

R¹ is —X-R⁸, wherein X is selected from the group consisting of:

(1) —CH₂—, and

(2) —CO—,

and wherein R⁸ is a selected from:

phenyl, naphthyl, indenyl, indanyl, indolyl, quinolyl, isoquinolyl,benzofuranyl, dihydrobenzofuranyl, methylenedioxybenzoyl,benzopyrazolyl, and benzotriazolyl, which may be unsubstituted orsubstituted, where the substituents are independently selected from:

(a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(A) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(B) naphthyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(C) heterocycle,unsubstituted or substituted, wherein the substituentsare independently selected from: halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆alkyl), or trifluoromethyl,

(D) hydroxy,

(E) —O(C₁₋₆ alkyl),

(F) —CO₂(C₁₋₆ alkyl),

(G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is an integer selected from 0, 1and 2,

(H) halogen,

(I) —NH₂,

(J) —NH(C₁₋₆ alkyl), and

(K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl),

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0, 1 and 2,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvi) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹and

(xxx) —CO-R⁹,

(b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰,

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹ ¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvii) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(c) —NO₂,

(d) hydroxy,

(e) halogen,

(f) —NR⁹R¹⁰,

(g) —NR⁹-COR¹⁰,

(h) —NR⁹-CO₂R¹⁰,

(i) —CO—NR⁹R¹⁰,

—OCO—NR⁹R¹⁰,

(k) —NR⁹CO—NR⁹R¹⁰,

(l) —S(O)₂—NR⁹R¹⁰,

(m) —NR⁹S(O)₂-R¹⁰,

(n) —NR⁹S(O)₂—NR⁹R¹⁰,

(o) —S(O)_(n)-R⁹,

(p) —CF₃,

(q) —CHF₂,

(r) —CH₂F,

(s) —OCO-R⁹,

(t) —OCO₂-R⁹, and

(u) —CO-R⁹;

wherein R⁵ is a selected from:

(1) phenyl, which is unsubstituted or substituted with halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, NHR⁹, —NR⁹R¹⁰, ortrifluoromethyl,

(2) -C₁₋₆alkyl-phenyl, -C₁₋₆alkyl-naphthyl, -C₁₋₆alkyl-indenyl,-C₁₋₆alkyl-indanyl, and -C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl; and wherein the-C₁₋₆alkyl is optionally substituted with oxo, hydroxy, C₁₋₆alkoxy,acetoxy, or halogen,

(3) —O-C₁₋₆alkyl-phenyl, —O-C₁₋₆alkyl-naphthyl, —O-C₁₋₆alkyl-indenyl,—O-C₁₋₆alkyl-indanyl, and —O-C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl,

(4) -C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl, and

(5) -C₁₋₄alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl;

R¹² and R¹³ are independently selected from:

(1) hydrogen,

(2) —CO₂(C₁₋₆ alkyl),

(3) hydroxy,

(4) halogen,

(5) —NR⁹R¹⁰,

(6) —NR⁹-COR¹⁰,

(7) —NR⁹-CO₂R¹⁰,

(8) —CF₃,

(9) —CHF₂,

(10) —CH₂F,

(11) —O-R⁹,

(12) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(a) —CO₂(C₁₋₆ alkyl),

(b) hydroxy,

(c) halogen,

(d) —NR⁹R¹⁰,

(e) —NR⁹-COR¹⁰,

(f) —NR⁹-CO₂R¹⁰,

(g) phenyl,

(h) —CF₃,

(i) —CHF₂,

(j) —CH₂F, and

(k) —O-R⁹,

(14) phenyl or heterocycle, wherein the phenyl or heterocycle isunsubstituted or substituted, wherein the substituents are independentlyselected from:

(a) —CO₂(C₁₋₆ alkyl),

(b) hydroxy,

(c) halogen,

(d) —NR⁹R¹⁰,

(e) —NR⁹-COR¹⁰,

(f) —NR⁹-CO₂R¹⁰,

(g) phenyl,

(h) —CF₃,

(i) —CHF₂,

(j) —CH₂F, and

(k) —O-R⁹,

Y and Z are independently selected from: C₁ alkyl, —O—, —S(O)_(n)— and—N(R⁹)—;

m is an integer selected from 1 and 2;

and pharmaceutically acceptable salts and individual diastereomersthereof.

In the present invention it is preferred that R¹ is —X-R⁸, wherein X isselected from the group consisting of:

(1) —CH₂—, and

(2) —CO—,

and wherein R⁸ is a selected from:

phenyl, naphthyl, biphenyl, indenyl, indanyl, and heterocycle, which maybe unsubstituted or substituted, where the substituents areindependently selected from:

(a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(A) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(B) naphthyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(C) heterocycle,unsubstituted or substituted, wherein the substituentsare independently selected from: halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆alkyl), or trifluoromethyl,

(D) hydroxy,

(E) —O(C₁₋₆ alkyl),

(F) —CO₂(C₁₋₆ alkyl),

(G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is an integer selected from 0, 1and 2,

(H) halogen,

(I) —NH₂,

(J) —NH(C₁₋₆ alkyl), and

(K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl),

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0, 1 and 2,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvi) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰,

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO₂R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvii) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(c) —NO₂,

(d) hydroxy,

(e) halogen,

(f) —NR⁹R¹⁰,

(g) —NR⁹-COR¹⁰,

(h) —NR⁹-CO₂R¹⁰,

(i) —CO—NR⁹R¹⁰,

(j) —OCO—NR⁹R¹⁰,

(k) —NR⁹CO—NR⁹R¹⁰,

(l) —S(O)₂—NR⁹R¹⁰,

(m) —NR⁹S(O)₂-R¹⁰,

(n) —NR⁹S(O)₂—NR⁹R¹⁰,

(o) —S(O)_(n)-R⁹,

(p) —CF₃,

(q) —CHF₂,

(r) —CH₂F,

(s) —OCO-R⁹,

(t) —OCO₂-R⁹, and

(u) —CO-R⁹.

In the present invention it is even more preferred that R¹ is —X-R⁸,wherein X is selected from the group consisting of:

(1) —CH₂—, and

(2) —CO—,

and wherein R⁸ is a selected from:

phenyl, naphthyl, indenyl, indanyl, indolyl, quinolyl, isoquinolyl,benzofuranyl, dihydrobenzofuranyl, methylenedioxybenzoyl,benzopyrazolyl, and benzotriazolyl, which may be unsubstituted orsubstituted, where the substituents are independently selected from:

(a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl,or alkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(A) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(B) naphthyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl,

(C) heterocycle,unsubstituted or substituted, wherein the substituentsare independently selected from: halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆alkyl), or trifluoromethyl,

(D) hydroxy,

(E) —O(C₁₋₆ alkyl),

(F) —CO₂(C₁₋₆ alkyl),

(G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is an integer selected from 0, 1and 2,

(H) halogen,

(I) —NH₂,

(J) —NH(C₁₋₆ alkyl), and

(K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl),

(v) —NR⁹-COR¹⁰,

(vi) —NR⁹—CO₂R¹⁰,

(vii) —CO—NR⁹R¹⁰,

(viii) —OCO—NR⁹R¹⁰,

(ix) —NR⁹CO—NR⁹R¹⁰,

(x) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0, 1 and 2,

(xi) —NR⁹S(O)₂-R¹⁰,

(xii) —NR⁹S(O)₂—NR⁹R¹⁰,

(xiii) —S(O)_(n)-R⁹,

(xiv) —CF₃,

(xv) —CHF₂,

(xvi) —CH₂F,

(xvii) —O-R⁹,

(xviii) —O(C₁₋₆ alkyl)-O-R⁹,

(xix) phenyl,

(xx) naphthyl,

(xxi) indenyl,

(xxii) indanyl,

(xxiii) heterocycle,

(xxiv) —CO-phenyl,

(xxv) —CO-naphthyl,

(xxvi) —CO-indenyl,

(xxvii) —CO-indanyl,

(xxviii) —CO-heterocycle,

(xxix) —OCO-R⁹,

(xxx) —OCO₂-R⁹, and

(xxxi) —CO-R⁹,

(b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from:

(i) hydroxy,

(ii) halogen,

(iii) —NR⁹R¹⁰,

(iv) —NR⁹-COR¹⁰,

(v) —NR⁹-CO²R¹⁰,

(vi) —CO—NR⁹R¹⁰,

(vii) —OCO—NR⁹R¹⁰,

(viii) —NR⁹CO—NR⁹R¹⁰,

(ix) —S(O)₂—NR⁹R¹⁰,

(x) —NR⁹S(O)₂-R¹⁰,

(xi) —NR⁹S(O)₂—NR⁹R¹⁰,

(xii) —S(O)_(n)-R⁹,

(xiii) —CF₃,

(xiv) —CHF₂,

(xv) —CH₂F,

(xvii) —O-R⁹,

(xvii) —O(C₁₋₆ alkyl)-O-R⁹,

(xviii) phenyl,

(xix) naphthyl,

(xx) indenyl,

(xxi) indanyl,

(xxii) heterocycle,

(xxiii) —CO-phenyl,

(xxiv) —CO-naphthyl,

(xxv) —CO-indenyl,

(xxvi) —CO-indanyl,

(xxvii) —CO-heterocycle,

(xxviii) —OCO-R⁹,

(xxix) —OCO₂-R⁹, and

(xxx) —CO-R⁹,

(c) —NO₂,

(d) hydroxy,

(e) halogen,

(f) —NR⁹R¹⁰,

(g) —NR⁹-COR¹⁰,

(h) —NR⁹-CO₂R¹⁰,

(i) —CO—NR⁹R¹⁰,

(j) —OCO—NR⁹R¹⁰,

(k) —NR⁹CO—NR⁹R¹⁰,

(l) —S(O)₂NR⁹R¹⁰,

(m) —NR⁹S(O)₂—R¹⁰,

(n) —NR⁹S(O)₂—NR⁹R¹⁰,

(o) —S(O)_(n)-R⁹,

(p) —CF₃,

(q) —CHF₂,

(r) —CH₂F,

(s) —OCO-R⁹,

(t) —OCO₂-R⁹, and

(u) —CO-R⁹.

In the present invention it is highly preferred that R¹ is selected fromthe group consisting of:

(1) —CH₂-phenyl,

(2) —CO-phenyl,

(3) —CH₂-(2,4-dichlorophenyl),

(4) —CO-(2,4-dichlorophenyl),

(5) —CH₂-(2-naphthyl),

(6) —CO-(1-naphthyl),

(7) —CH₂-indolyl, and

(8) —CO-indolyl.

In the present invention it is most preferred that R¹ is selected fromthe group consisting of:

(1) —CH₂-phenyl,

(2) —CO-phenyl,

(3) —CH₂-(2,4-dichlorophenyl),

(4) —CH₂-(7-indolyl), and

(5) —CO-(7-indolyl).

In the present invention it is preferred that R² is:

wherein R⁵ is selected from:

(1) phenyl, which is unsubstituted or substituted with halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, or trifluoromethyl,

(2) -C₁₋₆alkyl-phenyl, wherein the phenyl is unsubsituted or substitutedwith: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, or trifluoromethyl; andwherein the -C₁₋₆alkyl is optionally substituted with oxo, hydroxy,C₁₋₆alkoxy, acetoxy, or halogen,

(3) —O-C₁₋₆alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl,

(4) -C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, -C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl, and

(5) -C₁₋₄alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein n is an integerselected from 0, 1 and 2, and wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl.

In the present invention it is more preferred that R² is:

wherein R⁵ is a selected from:

(1) phenyl, which is unsubstituted or substituted with halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, or trifluoromethyl,

(2) -C₂₋₄alkyl-phenyl, wherein the phenyl is unsubsituted or substitutedwith chloro, fluoro, trifluoromethyl, methyl or ethyl and wherein the-C₂₋₄alkyl is optionally substituted with oxo, hydroxy, halogen, ormethoxy,

(3) -C₁₋₃alkyl-O-C₁₋₃alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with chloro, fluoro, trifluoromethyl, methyl or ethyl, and

(4) -C₁₋₃alkyl-S(O)_(n)-C₁₋₃alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with chloro, fluoro, trifluoromethyl, methylor ethyl.

In the present invention it is still more preferred that R² is:

wherein R⁵ is a selected from:

(1) phenyl, which is unsubstituted or substituted with halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, or trifluoromethyl,

(2) -C₃₋₄alkyl-phenyl, wherein the phenyl is unsubsituted or substitutedwith chloro, fluoro or methyl, and wherein the -C₃₋₄alkyl is optionallysubstituted with oxo, hydroxy, or methoxy,

(3) -C₁₋₃alkyl-O-C₁₋₃alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with chloro, fluoro or methyl, and

(4) -C₁₋₃alkyl-S(O)_(n)-C₁₋₃alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with chloro, fluoro or methyl.

In the present invention it is highly preferred that R² is:

In the present invention it is preferred that R³ is selected from thegroup consisting of:

(1) —CHO,

(2) —CO-R¹⁶, wherein R¹⁶ is C₁₋₆ alkyl, wherein the alkyl isunsubstituted or substituted, wherein the substituents are independentlyselected from:

(a) —CO₂(C₁₋₆ alkyl),

(b) hydroxy,

(c) —O-C₁₋₆ alkyl,

(d) halogen, and

(e) phenyl,

(3) —CO₂-R¹⁶,

(4) —CONH₂,

(5) —CONR¹⁶R¹⁷, wherein R¹⁷ is hydrogen or is independently selectedfrom the definitions of R¹⁶;

(6) —CONH—COR¹⁶,

(7) —C(R¹⁷)(OR¹⁶)(OR¹⁶),

(8) —C(R¹⁷)(SR¹⁶)(SR¹⁶),

(9) —C(R¹⁷)(OR¹⁴)(OR¹⁵), wherein R¹⁴ and R¹⁵ are joined together in aC₂₋₃ alkyl group to form a 5- or 6-membered ring which is substitutedwith R¹² and R¹³ wherein:

R¹² and R¹³ are independently selected from:

(a) hydrogen,

(b) —CO₂R¹⁶,

(c) hydroxy,

(d) halogen,

(e) —CF₃,

(f) —CHF₂,

(g) —CH₂F,

(h) C₁₋₆ alkyl, wherein the alkyl is unsubstituted or substituted,wherein the substituents are independently selected from:

(i) -CO₂(C₁₋₆ alkyl),

(ii) hydroxy,

(iii) —O-C₁₋₆ alkyl,

(iv) halogen, and

(v) phenyl,

(i) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) C₁₋₆ alkyl,

(ii) —CO₂(C₁₋₆ alkyl),

(iii) hydroxy,

(iv) —O-C₁₋₆ alkyl, and

(v) halogen,

(10) —C(R¹⁷)(SR¹⁴)(SR¹⁵),

(11) -cyclopentyl, which is substituted with R¹² and R¹³,

(12) -cyclohexyl, which is substituted with R¹² and R¹³,

(13) -tetrahydrofuranyl, which is substituted with R¹² and R¹³,

(14) -tetrahydropyranyl, which is substituted with R¹² and R¹³.

In the present invention it is more preferred that R³ is selected from:

(1) —CH(OR¹⁴)(OR¹⁵), wherein R¹⁴ and R¹⁵ are joined together in a C₂₋₃alkyl group to form a 5- or 6-membered ring which is substituted withR¹² and R¹³ wherein:

R¹² and R¹³ are independently selected from:

(a) hydrogen,

(b) C₁₋₆ alkyl, wherein the alkyl is unsubstituted or substituted,wherein the substituents are independently selected from:

(i) —O-C₁₋₆ alkyl,

(ii) halogen, and

(iii) phenyl,

(c) phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from:

(i) C₁₋₆ alkyl,

(ii) —O-C₁₋₆ alkyl,

(iii) halogen, and

(2) —CH(SR¹⁴)(SR¹⁵),

(3) -tetrahydrofuranyl, which is substituted with R¹² and R¹³,

(4) -tetrahydropyranyl, which is substituted with R¹² and R¹³.

In the present invention it is preferred that R^(4c), R^(4d), and R^(4h)are independently selected from the group consisting of:

(1) hydrogen, and

(2) C₁₋₆ alkyl.

In the present invention it is more preferred that R^(4c), and R^(4h)are each hydrogen and that R^(4d) is selected from the group consistingof hydrogen, and —CH₃.

In the present invention it is most preferred that R^(4c), R^(4d), andR^(4h) are each hydrogen.

The compounds of the instant invention have at least two asymmetriccenters at the ring junction of the substitutents bearing R² and R³.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within the ambit ofthis invention. The relative configurations of the most preferredcompounds of this invention are of the trans orientation, i.e. asdepicted:

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include chloro, fluoro, bromo and iodo.Similarly, C₁₋₈, as in C₁₋₈alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branchedarrangement, such that C₁₋₈alkyl specifically includes methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl and octyl. The term “heterocycle”as used herein is intended to include the following groups:benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

Specific compounds within the present invention include a compoundswhich selected from the group consisting of:

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine;

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-methoxycarbonylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)4-(SR)-ethoxycarbonylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-isopropyloxycarbonylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-benzyloxycarbonylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N-ethylaminocarbonyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4fluorophenyl)piperidinylmethyl)-4-(SR)-(N,N-diethylaminocarbonyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-acetylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-benzoylpyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclopentyl)pyrrolidine;

1-(1-Methyl-7-indolecarbonoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclopentyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclohexyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dithiolan-2-yl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)4-(SR)-(2-tetrahydrofuranyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dithian-2-yl)pyrrolidine;

1(1Naphthoyl)-3-(RS)-(4-(4fluorophenyl)piperidinylmethyl)-4-(SR)-(2-tetrahydropyranyl)pyrrolidine;

1-(1-Methyl-7indolecarbonoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)4-(SR)(1,3-dithiolan-2-yl)pyrrolidine;

1-(1-Methyl-7-indolecarbonoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2-tetrahydrofuranyl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine;

1-(Benzyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine;

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-methyl-1,3-dioxolan-2-yl)pyrrolidine;

1(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-flouromethyl-1,3-dioxolan-2-yl)pyrrolidine;

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-methoxymethyl-1,3-dioxolan-2-yl)pyrrolidine;

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)4-(SR)-(1,3-dioxan-2-yl)pyrrolidine;

and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

The subject compounds are useful in a method of modulating chemokinereceptor activity in a patient in need of such modulation comprising theadministration of an effective amount of the compound.

The present invention is directed to the use of the foregoingspiro-substituted azacycles as modulators of chemokine receptoractivity. In particular, these compounds are useful as modulators of thechemokine receptors, including CCR-3 and/or CCR-5.

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assay for CCR-5 binding asdisclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993), andthe assay for CCR-3 binding as disclosed by Daugherty, et al., J. Exp.Med., 183, 2349-2354 (1996). Cell lines for expressing the receptor ofinterest include those naturally expressing the receptor, such as EOL-3or THP-1, or a cell engineered to express a recombinant receptor, suchas CHO, RBL-2H3, HEK-293. For example, a CCR3 transfected AML14.3D10cell line has been placed on restricted deposit with American TypeCulture Collection in Rockville, Maryland as ATCC No. CRL-12079, on Apr.5, 1996. The utility of the compounds in accordance with the presentinvention as inhibitors of the spread of HlV infection in cells may bedemonstrated by methodology known in the art, such as the HIVquantitation assay disclosed by Nunberg, et al., J. Virology, 65 (9),4887-4892 (1991).

In particular, the compounds of the following examples had activity inbinding to the CCR-3 or the CCR-5 receptor in the aforementioned assays,generally with an IC₅₀ of less than about 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asmodulators of chemokine receptor activity.

Mammalian chemokine receptors provide a target for interfering with orpromoting eosinophil and/or lymphocyte function in a mammal, such as ahuman. Compounds which inhibit or promote chemokine receptor function,are particularly useful for modulating eosinophil and/or lymphocytefunction for therapeutic purposes. Accordingly, the present invention isdirected to compounds which are useful in the prevention and/ortreatment of a wide variety of inflammatory and immunoregulatorydisorders and diseases, allergic diseases, atopic conditions includingallergic rhinitis, dermatitis, conjunctivitis, and asthma, as well asautoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation. As aresult, one or more inflammatory processes, such as leukocyteemigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) orinflammatory mediator release, is inhibited. For example, eosinophilicinfiltration to inflammatory sites (e.g., in asthma) can be inhibitedaccording to the present method.

Similarly, an instant compound which promotes one or more functions of amammalian chemokine receptor (e.g., a human chemokine) is administeredto stimulate (induce or enhance) an inflammatory response, such asleukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes,histamine) or inflammatory mediator release, resulting in the beneficialstimulation of inflammatory processes. For example, eosinophils can berecruited to combat parasitic infections.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

Diseases and conditions associated with inflammation and infection canbe treated using the method of the present invention. In a preferredembodiment, the disease or condition is one in which the actions ofeosinophils and/or lymphocytes are to be inhibited or promoted, in orderto modulate the inflammatory response.

Diseases or conditions of humans or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, particularly bronchialasthma, allergic rhinitis, hypersensitivity lung diseases,hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler'ssyndrome, chronic eosinophilic pneumonia), delayed-typehypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS, individuals undergoingradiation therapy, chemotherapy, therapy for autoimmune disease or otherdrug therapy (e.g., corticosteroid therapy), which causesimmunosuppression; immunosuppression due congenital deficiency inreceptor function or other causes; and infectious diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapewornms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migrans (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larvamigrans (Ancylostona braziliense, Ancylostonia caninum).

The compounds of the present invention are accordingly useful in theprevention and treatment of a wide variety of inflammatory andimmunoregulatory disorders and diseases, allergic conditions, atopicconditions, as well as autoimmune pathologies.

In another aspect, the instant invention may be used to evaluateputative specific agonists or antagonists of chemokine receptors,including CCR-3 and/or CCR-5. Accordingly, the present invention isdirected to the use of these compounds in the preparation and executionof screening assays for compounds which modulate the activity ofchemokine receptors. For example, the compounds of this invention areuseful for isolating receptor mutants, which are excellent screeningtools for more potent compounds. Furthermore, the compounds of thisinvention are useful in establishing or determining the binding site ofother compounds to chemokine receptors, e.g., by competitive inhibition.The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors,including CCR-3 and/or CCR-5. As appreciated in the art, thoroughevaluation of specific agonists and antagonists of the above chemokinereceptors has been hampered by the lack of availability of non-peptidyl(metabolically resistant) compounds with high binding affinity for thesereceptors. Thus the compounds of this invention are commercial productsto be sold for these purposes.

The present invention is further directed to a method for themanufacture of a medicament for modulating chemokine receptor activityin humans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The present invention is further directed to the use of these compoundsin the prevention or treatment of infection by a retrovirus, inparticular, the human immunodeficiency virus (HIV) and the treatment of,and delaying of the onset of consequent pathological conditions such asAIDS. Treating AIDS or preventing or treating infection by HIV isdefined as including, but not limited to, treating a wide range ofstates of HIV infection: AIDS, ARC (AIDS related complex), bothsymptomatic and asymptomatic, and actual or potential exposure to HIV.For example, the compounds of this invention are useful in treatinginfection by HIV after suspected past exposure to HIV by, e.g., bloodtransfusion, organ transplant, exchange of body fluids, bites,accidental needle stick, or exposure to patient blood during surgery.

In a preferred aspect of the present invention, a subject compound maybe used in a method of inhibiting the binding of a chemokine to achemokine receptor, such as CCR-3 or CCR-5, of a target cell, whichcomprises contacting the target cell with an amount of the compoundwhich is effective at inhibiting the binding of the chemokine to thechemokine receptor.

The subject treated in the methods above is a mammal, preferably a humanbeing, male or female, in whom modulation of chemokine receptor activityis desired. “Modulation” as used herein is intended to encompassantagonism, agonism, partial antagonism and/or partial agonism. In apreferred aspect of the present invention, modulation refers toantagonism of chemokine receptor activity. The term “therapeuticallyeffective amount” means the amount of the subject compound that willelicit the biological or medical response of a tissue, system, animal orhuman that is being sought by the researcher, veterinarian, medicaldoctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

Combined therapy to modulate chemokine receptor activity and therebyprevent and treat inflammatory and immunoregulatory disorders anddiseases, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis, and thosepathologies noted above is illustrated by the combination of thecompounds of this invention and other compounds which are known for suchutilities.

For example, in the treatment or prevention of inflammation, the presentcompounds may be used in conjunction with an antiinflammatory oranalgesic agent such as an opiate agonist, a lipoxygenase inhibitor,such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, suchas a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the instant compounds maybe administered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine. Likewise,compounds of the present invention may be used in combination with otherdrugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds of thepressent invention are useful. Such other drugs may be administered, bya route and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention. Examples of otheractive ingredients that may be combined with a compound of the presentinvention, either administered separately or in the same pharmaceuticalcompositions, include, but are not limited to: (a) VLA-4 antagonistssuch as those described in U.S. Pat. No. 5,510,332, WO95/15973,WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/40781,WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818,WO98/54207, and WO98/58902; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as β2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (i) other antagonists of thechemokine receptors, especially CCR-1, CCR-2, CCR-3 and CCR-5; (j)cholesterol lowering agents such as HMG-CoA reductase inhibitors(lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, andother statins), sequestrants (cholestyramine and colestipol), nicotinicacid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrateand benzafibrate), and probucol; (k) anti-diabetic agents such asinsulin, sulfonylureas, biguanides (metformin), α-glucosidase inhibitors(acarbose) and glitazones (troglitazone and pioglitazone); (I)preparations of interferon beta (interferon beta-1α, interferonbeta-1β); (m) other compounds such as 5-aminosalicylic acid and prodrugsthereof, antimetabolites such as azathioprine and 6-mercaptopurine, andcytotoxic cancer chemotherapeutic agents. The weight ratio of thecompound of the compound of the present invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined with anNSAID the weight ratio of the compound of the present invention to theNSAID will generally range from about 1000:1 to about 1:1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The present invention is further directed to combinations of the presentcompounds with one or more agents useful in the prevention or treatmentof AIDS. For example, the compounds of this invention may be effectivelyadministered, whether at periods of pre-exposure and/or post-exposure,in combination with effective amounts of the AIDS antivirals,immunomodulators, anti-infectives, or vaccines known to those ofordinary skill in the art.

Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)141 W94 Glaxo Wellcome HIV infection, AIDS, ARC (protease inhibitor)1592U89 Glaxo Wellcome HIV infection, AIDS, ARC Acemannan CarringtonLabs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS,ARC, in combination with AZT AD-439 Tanox Biosystems HIV infection,AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovirdipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL (LosAngeles, CA) HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi'ssarcoma, HIV in combination w/Retrovir Ansamycin Adria Laboratories ARCLM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which AdvancedBiotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant(Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARCbeta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases (−)6-Chloro-4(S)- Merck HIV infection, AIDS, cyclopropylethynyl- ARC4(S)-trifluoro-methyl- (non-nucleoside 1,4-dihydro-2H-3,1- reversetranscriptase benzoxazin-2-one inhibitor) CI-1012 Warner-Lambert HIV-1infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirusCurdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmuneCMV retinitis immune globin Cytovene Syntex sight threatening CMVGanciclovir peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIVinfection, AIDS, ARC (protease inhibitor) Dextran Sulfate Ueno FineChem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomatic Japan) ddCHoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combination with AZT/d4T DMP-450 AVID HIV infection, AIDS, (Camden, NJ)ARC (protease inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville,GA) Efavirenz, DMP-266 Dupont-Merck HIV infection, AIDS, PharmaceuticalsARC (non-nucleoside reverse transcriptase inhibitor) Famciclovir SmithKline herpes zoster, herpes simplex FTC Emory University HIV infection,AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection,AIDS, ARC (reverse transcriptase inhibitor) GW 141 Glaxo Welcome HIVinfection, AIDS, ARC (protease inhibitor) GW 1592 Glaxo Welcome HIVinfection, MDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion HIV infection, AIDS, Roussel ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC,AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersSquibb CMV infection Nelfinavir Agouron HIV infection, AIDS,Pharmaceuticals ARC (protease inhibitor) Nevirapine BoeheringerIngleheim HIV infection, AIDS, ARC (protease inhibitor) NovaprenNovaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula LabsAIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMVretinitis, HIV Phosphonoformate Products, Inc infection, other CMVinfections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC(protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4Sheffield Med. Tech HIV infection, AIDS, (Houston TX) ARC RitonavirAbbott HIV infection, AIDS, ARC (protease inhibitor) SaquinavirHoffmann-LaRoche HIV infection, AIDS, ARC (protease inhibitor)Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy-ARC thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV infectionsVirazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA)positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC ZalcitabineHoffmann-La Roche HIV infection, AIDS, ARC, with AZT Zidovudine; AZTGlaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, incombination with other therapies IMMUNO-MODULATORS AS-101 Wyeth-AyerstAIDS Bropirimine Pharmacia Upjohn advanced AIDS Acemannan CarringtonLabs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS,Kaposi's Lederle Labs sarcoma EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Gamma Interferon Genentech ARC, in combination w/TNF(tumor necrosis factor) Granulocyte Genetics Institute AIDS MacrophageColony Sandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDSMacrophage Colony Immunex Stimulating Factor Granulocyte Schering-PloughAIDS, combination Macrophage Colony w/AZT Stimulating Factor HIV CoreParticle Rorer seropositive HIV Immunostimulant IL-2 Cetus AIDS, incombination Interleukin-2 w/AZT IL-2 Hoffman-La Roche AIDS, ARC, HIV, inInterleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase inCD4 Interleukin-2 cell counts (aldeslukin) Immune Globulin CutterBiological pediatric AIDS, in Intravenous (Berkeley, CA) combinationw/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC,PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio CarbamateAlpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDSMethionine- TIN Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PECiba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte AmgenAIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse immunotherapeutic Corp. AIDS, ARC rCD4 Genentech RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research InstituteTumor Necrosis Genentech ARC, in combination Factor; TNF w/gammaInterferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer cryptococcal meningitis, candidiasisPastille Squibb Corp. prevention of Nystatin Pastille oral candidiasisOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterialTrimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis isethionate forinhalation Spiramycin Rhone-Poulenc cryptosporidial diarrheaIntraconazole- Janssen Pharm. histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP OTHER Daunorubicin NeXstar,Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severeanemia Erythropoietin assoc. with AZT therapy Recombinant Human SeronoAIDS-related wasting, Growth Hormone cachexia Leukotriene B4 — HIVinfection Receptor Antagonist Megestrol Acetate Bristol-Myers Squibbtreatment of anorexia assoc. w/AIDS Soluble CD4 Protein — HIV infectionand Derivatives Testosterone Alza, Smith Kline AIDS-related wastingTotal Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticalsmalabsorption related to AIDS

It will be understood that the scope of combinations of the compounds ofthis invention with AIDS antivirals, immunomodulators, anti-infectivesor vaccines is not limited to the list in the above Table, but includesin principle any combination with any pharmaceutical composition usefulfor the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments ofwith a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI.Preferred agents for combination therapy include: Zidovudine,Lamivudine, Stavudine, Efavirenz, Ritonavir, Nelfinavir, Abacavir,Indinavir, 141-W94 (4-amino-N-((2syn,3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)-butyl)-N-isobutyl-benzenesulfonamide),N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl4-(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-N′(t-butylcarbox-amido)-piperazinyl))-pentaneamide,and Delavirdine. A preferred inhibitor of HlV protease is indinavir,which is the sulfate salt ofN-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pridyl-methyl)-2(S)-N′-(t-butylcarbo-xamido)-piperazinyl))-pentane-amideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred inhibitors of HIV protease include nelfinavir andritonavir. Preferred non-nucleoside inhibitors of HIV reversetranscriptase include(−)6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,which may be prepared by methods disclosed in EP 0,582,455. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations with thecompounds of the present invention include the following: (1) Zidovudineand Lamivudine; (2) Stavudine and Lamivudine; (3) Efavirenz; (4)Ritoavir; (5) Nelfinavir; (6) Abacavir; (7) Indinavir; (8) 141-W94; and(9) Delavirdine. Preferred combinations with the compounds of thepresent invention further include the following (1) indinavir, withefavirenz or (−)6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir,and any of AZT and/or ddI and/or ddC.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products. of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of The present invention are employed.(For purposes of this application, topical application shall includemouth washes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made from known procedures or as illustrated.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples.

In one protocol, the compounds of the present invention are prepared byalkylating heterocycle 1 (wherein X is a leaving group such as, forexample, bromide, iodide, methanesulfonate, p-toluenesulfonate,trifluoromethanesulfonate) with cyclic amine 2 under appropriateconditions to provide compound 3. Cyclic amine 2 is availablecommercially or can be prepared using the methods given below.

Alternatively, heterocycle 4, bearing a carbonyl group, can be combinedwith the cyclic amine 2 and the intermediate imine or iminium species isreduced to tertiary amine 3 under homogenous conditions (e.g. usingsodium cyanoborohydride, sodium borohydride, or sodiumtriacetoxyborohydride) or in the presence of hydrogen and aheterogeneous catalyst (e.g. palladium on carbon or Raney nickel).

In an alternative embodiment of the present invention, heterocycle 5,bearing an activated acyl side chain (wherein X′, for example, is achloride or bromide atom, or is a hydroxybenzotriazole residue fromactivation of the corresponding carboxylic acid with HOBt in thepresence of a suitable carbodiimide) is allowed to react with cyclicamine 2 to provide the corresponding tertiary amide 6. Compound 6 canthen be treated with a suitable reducing agent (e.g. diborane; borane inTHF; borane dimethylsulfide, or lithium aluminum hydride) to provide thedesired product 7.

An alternative preparation of the target compounds is carried out asshown in Scheme 2. Treatment of alcohol 8 with zinc azide bis(pyridine)complex in the presence of triphenylphosphine and diethylazodicarboxylate, or with diphenylphosphoryl azide, or with hydrazoicacid, provides azide 9. Reduction of 9, for example, with hydrogen andpalladium on carbon, affords primary amine 10. This amine can be doublyalkylated with a bis-electrophile such as 13 under basic conditions, toprovide the compound 14. Bis-electrophiles can be prepared fromsubstituted glutaric anhydride derivatives such as 11 by reduction todiol 12 followed by double activation, using, for example,p-toluenesulfonyl chloride in pyridine, or triphenylphosphine carbontetrabromide in acetonitrile, to provide 13 (where X=Br or OTs).

The preparation of compounds within the scope of the instant inventionwhich bear a 1,3,4-trisubstituted pyrrolidine framework is detailed inScheme 3. Treatment of a trans-cinnamic ester such as 15 withN-benzyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine (16) in thepresence of a catalytic amount of an acid such as TFA, titaniumtetrafluoride lithium fluoride or cesium fluoride according to theprocedure of Padwa et al (J. Org. Chem. 1987,52, 235) preferentiallyaffords the 3,4-trans pyrrolidine 17. Executing this sequence startingfrom the cis-cinnamic ester results in preferential formation of the3,4-cis pyrrolidine. Reduction of ester 17 with diisobutylaluminumhydride, lithium aluminium hydride, or sodiumbis(2-methoxyethoxy)aluminum hydride, provides the primary alcohol 18.Oxidation of 18 to the aldehyde 19 can be carried out under numerousconditions, such as with the Swern reaction, with DMSO and oxalylchloride at low temperature, followed by triethylamine, or with variouschromium trioxide-based reagents (see March J. “Advanced OrganicChemistry”, 4th ed., John Wiley & Sons, New York, pp. 1167-1171 (1992)).Reductive amination with cyclic amine 2 provides diamine 20.Alternatively, The N-benzyl group is cleaved in a hydrogen atmosphere inthe presence of 10% palladium on carbon or with Pearlmans' catalyst[Pd(OH)₂/C] to provide the secondary amine 21.

In cases when certain substituents are labile to hydrogenolysisconditions, alternative methods to remove the benzyl group of compound20 are described in Scheme 4. Compound 20 may be converted to theallyloxycarbamate derivative by stirring with allylchloroformate at rtin a solvent such as THF (T. Shono, Y. Matsumura, J. Org. Chem., 1984,48, 300) Subsequent reaction with hydrazine hydrate and KOH in ethyleneglycol at elevated temperatures provides the amine 21. Compound 20 mayalso be converted to its 2,2,2,-trichloroethyloxycarbamate derivative bystirring with 2,2,2-trichloroethylchloroformate in a solvent such asacetonitrile (V. H. Rawal, R. J. Jones, J. Org. Chem., 1987, 52, 19).This derivative is then converted to amine 21 by reaction with zincpowder in acetic acid a slightly elevated temperatures such as at 40° C.

Scheme 5 describes a modification of Scheme 3 when substituents are notcompatible with hydrogenolysis of the benzyl group of compound 20. Inthis variation, treatment of a trans-cinnamic ester 15 withN-allyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine (16′) accordingto procedures described in Scheme 3 provides N-allylpyrrolidinederivative 17′. The reagentN-allyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine is prepared afterprocedures described by Padwa et al (J. Org. Chem. 1985, 50, 4006 and J.Org. Chem. 1987,.52, 235) Subsequent elaboration as described in Scheme3 gives compound 20′. The allyl group of compound 20′ is removed byheating with Wilkinson's catalyst ([Rh(PPh₃)₃Cl] in a solvent such as85% CH₃CN in water.

The unsubstituted pyrrolidine 21 may be further functionalized as shownin Scheme 6. Reductive amination with suitable aldehydes under standardconditions provides the tertiary amine 22. The pyrrolidine nitrogen maybe alkylated with a suitable halide, methanesulfonate,p-toluene-sulfonate, etc. carried out under standard conditions toprovide N-alkylated pyrrolidine 22. Alternatively, compound 22 isacylated with, for example, acid chlorides or bromides, or activatedesters utilizing a variety of the standard coupling conditions to giveamide 23. For example, reaction of compound 22 and a carboxylic acidwith BOP—Cl and triethylamine in a solvent such as methylene chloride isa commonly used procedure. The sulfonamide 24 is prepared under standardconditions by exposing 21 to an alkyl or aryl sulfonyl chloride in thepresence of a suitable base to neutralize the formed hydrogen chloride.

Compounds possessing geminal substituents on positions 3 or 4 (or onboth C3 and C4) of the pyrrolidine ring are prepared by the method shownin Scheme 7. Cycloaddition of unsaturated aldehyde 25 with reagent 16 or16′ as described in Schemes 3 or 5 provides pyrrolidine aldehyde 26.Further elaboration of 26 can be achieved as described in the previousSchemes.

An alternative approach to the synthesis of chemokine modulators isdescribed in Example 8. Ester derivatives 17 (Scheme 3) or 17′ (Scheme5) are first debenzylated or deallylated by procedures described inSchemes 3, 4 or 5 to give secondary amine derivative 27. Compound 27 canthen be elaborated as described in Scheme 6 to provide compound 28. Theester group of 28 can be selectively reduced with a reagent such aslithium borohydride in THF to give the alcohol 29 which is thenconverted to aldehyde 36 under Swern conditions as described in Scheme3. Aldehyde 39 is then converted to derivative 22 (or 23 or 24) byreductive amination (Scheme 3).

The preparation of optically active compounds described in Scheme 9follows procedures described by Ma et.al., (Tetrahedron: Assymmetry1997, 8, 883). Reaction of a trans-acrylic acid with oxalyl chloride orpivaloyl chloride and triethylamine in THF provide the mixed anhydrideintermediate. This is then treated with the lithium salt of anappropriate chiral auxiliary such as (S)-benzyl-2-oxazolidinone in THFat reduced temperatures, such as −78° C. to give amide 28. Thisacrylamide is then reacted withN-benzyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine (16) orN-allyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine (16′) asdescribed in Schemes 3 and 5, respectively, to give pyrrolidineintermediate 29 or the corresponding N-allyl derivative. Modestdiastereoselectivity is achieved in these cyclizations as shown by Ma etal. However, the separate optically active isomers may be easilyobtained by simple chromatography on silica gel. Reaction of theselected diastereomer 29 with LiAlH₄ in THF at 0° C. provides theoptically active version of compound 18 which is further elaborated asdescribed in the previous Schemes

The various piperidine derivatives, when not commercially available, areprepared as described in the following Schemes.

The synthesis of 4-arylpiperidine groups is presented in Scheme 10.Enolate formation of the 4-piperidone derivative 29 followed byformation of the vinyl triflate with either 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine or with N-phenyltriflimide providestrifilate ether 30. Palladium-mediated coupling with a suitable arylstannane or aryl boronic acid provides the tetrahydropyridine derivative31. The Boc protecting group can be removed with TFA to give amine 32which is then hydrogenated under standard conditions to give pipesidine33. Alternatively, tetrahydropyridine derivative 31 is firsthydrogenated and then deprotected. Modification of the aryl group ofcompound 31 or 33 is achieved using appropriate chemical modificationschemes.

A method of preparing 4-(3-aryl-1-propyl)-4-hydroxypiperidinederivatives is described in Scheme 11. A suitable 3-arylpropyl halide 34in THF at −78° C. is reacted with a base such as t-butyl lithium. Thisis then reacted with a protected 4-piperidone derivative such asN-benzyl-4-piperidone 35 to give the arylpropylpiperidine derivative 36.Deprotection by hydrogenation with Pd(OH)₂/C (Pearlman's catalyst) givespiperidine derivative 37 which can be reacted with compound 19 asdescribed in Scheme 3.

A method of preparing 4-aryloxyethylpiperidine derivatives is describedin Scheme 12. Reaction of commercially availableN-benzyl-4-hydroxyethylpiperidine with an appropriate aryl alcohol understandard Mitsunobu conditions, followed by deprotection gives thecorresponding piperidine derivative. The corresponding mercaptoderivative is prepared by reaction of compound 38 with an aryldisulfideand tri-n-butylphosphine in THF with heating at reflux to give compound41. Compound 41 is then converted to compound 42 as described in Scheme4.

Compound 45 can be prepared prepared (Scheme 13) by alkylation ofcompound 44 (prepared from isonipecotic acid) with an arylmethylhalide,bromide, iodide, methanesulfonate, p-toluenesulfonate, ortrifluoromethanesulfonate in a solvent such as THF with a base such assodium hydride. Subsequently, compound 45 is deprotected by reactionwith trifluoroacetic acid in a solvent such as methylene chloride togive compound 46.

In Scheme 14, the preparation of 4-(3-aryl-2-hydroxypropyl) piperidinesis described. Compound 38 is converted to aldehyde 46 by the Swern-typeconditions (oxalyl chloride, DMSO, Et₃N). Reaction of compound 46 withGrignard reagents or other related nucleophiles gives hydroxy derivative47. Compound 47 is then converted to piperidine 48 by proceduresdescribed in Scheme 4.

Compound 47 can be further derivatized as depicted in Scheme 15. Etherderivatives 48 can be prepared by reaction with an alkylhalide, tosylateor triflate in the presence of a base such as sodium hydride in anaprotic inert solvent such as THF. Alternatively, an excess of silveroxide (Ag₂O) is used in place of the base. In an alternate procedure,reaction of an alcohol with trifluoromethane sulfonic anhydride (Tf₂O,triflic anhydride) in dichloromethane at reduced temperature, preferably−78° C. gives the preformed triflate. To this solution is added compound47, the reaction mixture is warmed to room temperature and stirring iscontinued until reaction is complete.

Esters (compound 49) can be prepared by reaction of a pre-formedcarboxylic acid chloride with compound 47 in a basic solvent such aspyridine or triethylamine. The acid chlorides, when not purchased, areprepared by stirring the carboxylic acids in reagents such as oxalylchloride or thionyl chloride. C4 sulfonate derivatives are prepared in asimilar manner by reaction with sulfonyl chlorides.

C4 carbamate and carbonate derivatives (compound 52) are prepared byfirst reacting compound 47 with carbonyldiimidazole (CDI) to obtain theimidazolecarbonyl intermediate which is then reacted with an amine(R¹R²NH) or an alcohol to give the corresponding carbonate or carbamatederivatives.

Compound 47 can be oxidized to the corresponding ketone 51 by any numberof standard conditions. It can then be reaction with Grignard reagentsor related nucleophiles (as in Scheme 14) to give the tertiary hydroxyderivative 52. This alcohol can then be further modified as described inthis scheme.

In Scheme 16, the preparation of 4-(3-phenyl-3-hydroxypropyl)piperidines is described. Oxidation of compound 44 under Swernconditions gives aldehyde derivative 53. It is then reacted withdiethyl(2-aryl-2-oxoethyl)phosphonate and a base such as KOtBu in asolvent such as THF to give the conjugated ketone derivative 54.Reduction with hydrogen in the presence of Pd/C preferentially at 50 psigives the hydroxy compound 55 which is converted to piperidinederivative 56 as previously described. Prior to deprotection, compound55 can be further modified as depicted in Scheme 15.

The synthesis of a framework for piperidine-based chemokine receptormodulators is given in Scheme 17. Enolate formation of the 4-piperidonederivative 35 followed by formation of the vinyl triflate with either2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine or withN-phenyltriflimide provides compound 57. Palladium-catalysedcarbonylation in the presence of methanol then affords unsaturated ester58. Conjugate addition of an aryl magnesium halide reagent in thepresence of a copper catalyst and chlorotrimethylsilane to this species,followed by treatment with the magnesium salt of a suitable cyclicamine, then yields amide 59. Reduction with LiAlH₄ or borane.THF affordsthe tertiary amine 60, which is hydrogenated under standard conditionsto the secondary piperidine 61. This compound is alkylated, acylated orsulfonated by analogy to the conditions described for compound 21 inScheme 4.

Synthesis of a piperidine derivative with an alternate presentation ofthe 3- and 4-substituents is given in Scheme 18. Formation of theenolate of ketoester 62 (prepared from commercially available3-carbomethoxy4-oxopiperidine and Boc anhydride) followed by addition ofeither 2-[N,N-bis(trifluoro-methylsulfonyl)amino]-5-chloropyridine orN-phenyltriflimide provides vinyl triflate 63. Palladium-mediatedcoupling with a suitable aryl stannane or aryl boronic acid providesunsaturated ester 64. Treatment of this compound with the magnesium saltof a suitable cyclic amine then affords amide 65, which can be reducedsuccessively with magnesium metal in methanol followed by alane in THF,to provide the tertiary amine 66. Removal of the Boc group understandard acidic conditions yields secondary amine 67, which can bealkylated, acylated or sulfonated by analogy to the conditions describedin Scheme 6.

The cyclic amine II employed in the preceding Schemes can be obtainedcommercially in many cases or is prepared by a number of procedures. Forexample, as shown in Scheme 19, compound 68, the N-t-butoxycarbonylprotected form of isonipecotic acid (4-piperidine-carboxylic acid) isactivated under standard conditions, for example with a carbodiimide,and converted into ester 69 or amide 70. Alternatively, acid 68 isconverted into the N-methyl-N-methoxy amide, 71, which upon reactionwith organomagnesium and organolithium reagents forms the ketone 72. TheBoc group of 69, 70 and 72 is removed under acidic conditions to providethe corresponding secondary amines.

Alternatively, CBZ-protected piperidine 73 is allowed to react withoxalyl chloride and then sodium azide, to provide the corresponding acylazide, which can then be thermally rearranged to isocyanate 74 (Scheme20). Compound 74 is treated with an alcohol ROH or an amine RR′NH toform carbamate 75 or urea 76, respectively, each of which is deprotectedwith hydrogen in the presence of palladium on carbon to secondary amines77 or 78.

If the carbamate 75 has R=—(CH₂)_(X)CH₂Cl, where x=1-3, then treatmentwith a suitable base, such as sodium hydride, lithiumhexamethyldisilazide or potassium t-butoxide, can induce cyclization tocompound 79 (Scheme 21). For other R groups, carbamate 75 is treatedwith an alkylating agent R′X,where R′= primary or secondary alkyl,allyl, propargyl or benzyl, while X=bromide, iodide, tosylate, mesylateor trifluoromethanesulfonate, in the presence of a suitable base, suchas sodium hydride, lithium hexamethyldisilazide or potassium t-butoxide,to give derivative 80; a similar process can be employed for urea 76. Ineach case, removal of the CBZ protecting group under standard conditionsprovides the secondary amines 81 and 82.

Additional derivatization of a piperidine with nitrogen functionality atC4 is carried out as shown in Scheme 22. For example, if the ringnitrogen is protected with a CBZ group, as with isocyanate 74, treatmentwith tert-butyl alcohol in the presence of copper(I) chloride, providesBoc derivative 83. This compound is selectively deprotected to the freeamine 84. This amine is acylated with an acid chloride, a chloroformate,an isocyanate, or a carbamyl chloride, to provide compounds 85, 75 or76. Alternatively, amine 84 is sulfonated with an alkyl or arylsulfonylchloride, to give sulfonamide 86. Compounds 85 and 86 optionally isalkylated under the conditions given above. As shown in Scheme 21,removal of the CBZ group under reductive conditions gives the desiredsecondary amines.

Substituted spiro(indoline-3,4′-piperidine) derivatives can be preparedas shown in Scheme 23 starting from the substituted phenylhydrazine 87and the aldyhyde 88. Following the Fischer indole reaction and reductionof the intermediate imine with a mild reducing agent such as sodiumborohydride, the indoline 89 can be combined with an electrophile suchas an acyl chloride or a sulfonyl chloride. The protecting group oncompound 90, for example a benzyloxycarbonyl group, can be removed bytreatment with hydrogen in the presence of palladium on carbon or byexposure to trimethylsilyl iodide, to give the deprotected substitutedspiro(indoline-3,4′-piperidine) 91.

Preparation of spiro(2,3-dihydrobenzothiophene-3,4′-piperidine)derivatives is shown in Scheme 24. Reaction piperidone 29 with thelithium salt of methyl phenyl sulfoxide affords adduct 92. Base-mediatedelimination-rearrangement and basic cleavage provides the allylicalcohol 93. The alcohol is converted to rearranged allylic chloride 94with thionyl chloride in toluene in the presence of 2,6-lutidine as aproton scavenger. Displacement of the chloride with the2-bromothiophenol 95 provides allylic sulfide 96, which can be cyclizedunder radical conditions to givespiro(2,3-dihydrobenzothiophene-3,4′-piperidine) 97. Cleavage of thet-butoxycarbonyl group under standard conditions, such astrifluoroacetic acid, then provides the desired spirocycle 98.

Spiro(2,3-dihydrobenzofuran-3,4′-piperidine) derivatives are prepared asillustrated in Scheme 25. Treatment of an appropiately substituted esterof 2-fluorophenylacetate 99 with mechlorethamine hydrochloride 100 underbasic conditions provides piperidine 101, which on treatment with astrong reducing agent such as lithium aluminum hydride produces thecorresponding 4-(hydroxymethyl) compound 102. Cyclization with baseprovides benzofuran 103, and cleavage of the N-methyl group is thencarried out using 1-chloroethyl chloroformate or other suitableN-demethylating agents, to provide the desired intermediate 104.

Spiro(2-oxo-1,2,3,4-tetrahydroquinoline-4,4′-piperidine) andspiro(1-oxo-1,2,3,4-tetrahydroisoquinoline-4,4′-piperidine) are preparedas shown in Scheme 26. Starting from thespiro(2-oxoindane-3,4′-piperidine) LXXXVIII (described in Claremon, D.A. et al, European Patent 0 431 943 943 A2, Evans, B. E. et al, U.S.Pat. No. 5,091,387, Davis, L. et al, U.S. Pat. No. 4,420,485, all ofwhich are incorporated by reference, and Parham et al, Journal ofOrganic Chemistry, 41, 2628 (1976)), deprotection of the piperidinenitrogen is carried out by treatment with acid, for exampletrifluoroacetic acid, to provide ketone 106. After protection as thetrifluoroacetamide, the product is exposed to hydrazoic acid in thepresence of sulfuric acid. Heating of this mixture effects a Schmidtrearrangement, to provide both tetrahydroquinoline 107 and thetetrahydroisoquinoline 108. These spiro compounds are then separated andcoupled to functionalized aldehydes by the methodology given above.

Cyclic amines (compound 2) which are 4-arylpiperazines functionality areprepared using methods described in the following Schemes. Startingmaterials are made from known procedures or as illustrated. Substitutedpurines are prepared as disclosed in U.S. Pat. No. 5,057,517;imidazo(1.2-a)pyrazinyl, as disclosed in U.S. Pat. No. 4,242,344;(1,2,4)-triazolo(1.5-a)pyrazinyl as disclosed in J. Org. Chem, 1974, 39,2143 and J. C. S. Perkin I 1980, 506; 1,7-naphthyridinyl as disclosed inJ. Org. Chem. 1963, 28, 1753; furo(3.2-c)pyridinyl as disclosed in J.Heterocyclic Chem., 1982 ,19, 1207; and substituted6-H-7,8-dihydro-thiopyrano(3.2-d)pyrimidyl as disclosed in Arch. Int.Pharmacodyn. 1986, 280, pp302-313.

Optionally, Compound III formed in the alkylation step is furthermodified in subsequent reactions. In one illustration of such anapproach, the piperazine fragment may contain a nitro group, which isreduced to the amine after the coupling step. The resulting amine isfurther modified by acylation to provide the desired compounds. Thepiperazine fragment may also contain a protecting group such as a benzylester or a t-butyl ester. After reductive amination the protecting groupis removed and the resulting acid is further reacted to provideadditional analogs. Alternatively, the aldehyde portion may also containa protecting group such as a t-butoxycarbonyl for an amino function.After reductive amination, the t-butoxycarbonyl group is removed bytreatment with a strong acid such as trifluoroacetic acid, formic acidor hydrochloric acid and the resulting amine may be acylated to provideother analogs.

The piperazine starting materials used in the coupling reaction areprepared using methods described in the literature; more specifically asdescribed in U.S. Pat. Nos. 5,057,517; 4,242,344; J. Org. Chem, 1974,39, 2143 and J. C. S. Perkin I, 1980, 506; J. Org. Chem. 1963, 28, 1753;J. Heterocyclic Chem., 1982 ,19, 1207; Arch. Int. Pharmacodyn. 1986,280, pp302-313; Meurer, L. C. et al., J. Med. Chem., 1992, 35,3845-3857. None of these published compounds are disclosed to bechemokine receptor modulators. Alternatively, the piperazine substratesis prepared as illustrated in Schemes 27-30.

Substituted 4-arylpiperazines are prepared from appropriatefluorobenzene derivatives as shown in Scheme 27. Thus, reaction of2-fluorobenzonitrile with 1-t-butoxycarbonylpiperazine in the presenceof a base such as K₂CO₃ gives1-t-butoxycarbonyl-4-(2-cyanophenyl)-piperazine (compound 109. Reductionof the cyano group by hydrogenation in the presence of Raney nickel orby other known methods gives benzyl amine 110, which is acylated orsulfonylated, to provide piperazine 111. The t-butoxycarbonyl protectinggroup is removed under acidic conditions, for example by treatment withtrifluoroacetic acid or anhydrous HCl to give 1-unsubstituted piperazine112 which can be used in the reductive amination or alkylation stepsdescribed in Scheme 1. Similar reactions using 2-chloro-nitrobenzene inthe place of 2-fluorobenzonitrile provides compounds containing asubstituted aniline. Analogs containing a benzoic acid or itsderivatives are prepared by substituting 2-fluorobenzoic acid in thissequence.

Arylpiperazine derivatives containing heterocyclic substituents aresynthesized as shown in Scheme 28. Reaction between 2-fluorobenzaldehydeand 1-t-butoxycarbonylpiperazine gives1-t-butoxycarbonyl-4-(2-formylphenyl)-piperazine compound 113. Reductionof this aldehyde and treatment of the alcohol 114 with methanesulfonylchloride gives 115 (X=mesylate), while treatment of 114 withtriphenylphosphine and carbon tetrabromide gives 115 (X=bromide).Displacement of the leaving group by a heterocycle such as imidazole inthe presence of a base provides piperazine 116. Removal of thet-butoxycarbonyl protecting group under standard anhydrous acidicconditions furnishes compound 117 which is used in the couplingreactions described in Scheme I.

Preparation of piperazines containing a heteroaryl substituent isoutlined in Scheme 29. Reaction of 1-t-butoxycarbonyl-piperazine with achloro substituted heteroaromatic compound such as8-chloro-1,7-naphthyridine or 8-chloro-(1,2,4)-triazolo(1,5-a)pyrazinegives N-protected piperazine 108. Removal of the t-butoxycarbonylprotecting group under standard conditions by treatment with acidprovides piperazine 109 for use in the coupling steps outlined in Scheme1.

A variation of Reaction Schemes 1 to 9 is described in Reaction Scheme30. Monoethylsuccinate 110 is coupled with cyclic amine 2 as describedin Reaction Scheme 1 to give amide 111. Amide 111 is cyclized withN-benzyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine (16) orN-allyl-N-methoxymethyl-N-(trimethylsilyl)-methylamine (16′) asdescribed in Reaction Schemes 3 or 5 to give pyrrolidine derivative 112.Reduction of compound 112 with LAH in THF or ether gives primary alcohol113. The protecting group on the nitrogen of compound 113 can be removedas described in Reaction Scheme 3 to give compound 114. In the casewhere the protecting group is allyl, it is removed as described inReaction Scheme 5. The nitrogen position of compound 114 can befunctionalized as described in Reaction Scheme 6, when the conditionsare compatible with the primary alcohol. For example, compound 114 isreacted with an acid chloride in a solvent such as methylene chloride.To the reaction mixture is then added methanol or ethanol with addedstirring to remove any unitended acylation of the primary alcohol.

In Reaction Scheme 31, compound 31 is oxidized to aldehyde derivative116 utilizing Swern-type conditions described in Scheme 3. Compound 115can also be oxidized to acid derivative 117 utilizing various chromiumtrioxide-based reagents (see March J. “Advanced Organic Chemistry”, 4thed., John Wiley & Sons, New York, pp. 1167-1171 (1992)).

Primary alcohol 115 may be further modified in numerous ways includingconversion to ether 118, ester 119 and carbamate 120 as described inReaction scheme 15. Alternatively, aryl ethers are prepared usingtriaryl bismuthine reagents (Sinclair et. al., Bioorg. Med. Chem.Letters 1995, 5, 1035 and references cited therein). Furthermodifications can be achieved utilizing standard methodologies.

Aldehyde 115 can be converted to acetals as demonstrated in Scheme 33.Heating a solution of 115 with a diol such as ethylene glycol and anacid such as paratoluenesulfonic acid in a solvent such as benzene ortoluene gives 1,3-dioxolane derivative 121. Other diols givecorresponding acetals. Thioacetal derivatives (122) may be prepared bysimilar means. Aldehyde 115 may be reacted with nucleophiles such asGrignard reagents to give secondary alcohol derivatives 123. Aldehyde115 can also be converted to amine 124 as described in Rxn Scheme 1.

In Scheme 34, aldehyde 115 can be converted to the difluoro derivative125 using SF₄ or the commercially available DAST (Et₂NSF₃) (see March J.“Advanced Organic Chemistry”, 4th ed., John Wiley & Sons, New York, pp.908-910 (1992)). Aldehyde 115 can be converted to olefin derivatives(126) by a variety of standard olefination conditions including Wittig,Homer-Emmons-Wadsworth and related reagents (see March J. “AdvancedOrganic Chemistry”, 4th ed., John Wiley & Sons, New York, pp. 956-963(1992)).

Secondary alcohol 115 can be converted to ether, ester and carbamatederivatives as described in Scheme 32. It may also be converted to theflouro derivative 127 using DAST as described in Reaction Scheme 34 andby March J. “Advanced Organic Chemistry”, 4th ed., John Wiley & Sons,New York, pp. 432 (1992)). It may also be oxidized to ketone 128 withvarious chromium trioxide-based reagents (see March J. “Advanced OrganicChemistry”, 4th ed., John Wiley & Sons, New York, pp. 1167-1171 (1992)).Ketone 128 can be converted to tertiary alcohol 129 by usingnucleophiles such as Grignard reagents. Ketone 128 can also be convertedto amine 130 as described in Reaction Scheme 1.

In Scheme 36, acid derivative 117 can be converted to ester derivative131 using standard conditions such as reaction with an alcohol with anacid such as TFA or HCl. Alternatively, acid 117 may be activated as anacid chloride using thionyl chloride or oxalyl chloride followed byreaction with an alcohol. Methyl esters can be prepared withdiazomethane. Activation of acid 117 with a reagent such asBOP-Cl[bis(2-oxo-3-oxazolidinyl)phosphinic chloride] and a base such asEt3N in methylene chloride followed by addtion of an alcohol or aminegives ester 131 or amide derivative 132. A variety of other standardamide coupling conditions may also be utilized.

Preparation of target pyrrolidines using solid support technology isoutlined in Scheme 22. Coupling of intermediate B to a commerciallyavailable 4-sulfamylbenzoyl polystyrene resin A (or a alkyl sulfamylresin) is carried out with di-lisopropylcarbodiimide or with otheractivating agents, for example dicyclohexylcarbodiimide, EDAC, oxalylchloride, etc. Agents that result in the formation of the symmetricalanhydride from B (which then serves as the acylating agent) are alsosuitable for this purpose. Removal of the Boc group is carried out withtrifluoroacetic acid or other acidic reagents, to give resin-boundpyrrolidine C. This intermediate is then coupled with sulfonyl chloridesor carbonyl chlorides in the presence of a suitable amine, preferably ahindered tertiary amine such as diisopropylethylamine (DIEA), lutidine,DBU, etc., to provide the N-functionalized pyrrolidine D. Alkylation ofthe acyl sulfonamide nitrogen can be carried out withtdmethylsilyldiazomethane, diazomethane, with bromoacetonitrile in thepresence of DBU and DNT, or under Mitsunobu conditions with a phenolsuch as pentafluorophenol. Reaction of the resulting N-alkylatedintermediate with an amine NH(R^(a))R^(b) at a temperature between 0 and140° C., preferably around 50 C, for 4-24 hr, preferably about 14 hr,then cleaves the pyrrolidine from the resin as amide E. Reduction of thenewly formed amide (and other amide functionality, if present) withborane methyl sulfide complex (or other hydride reducing agents, such asborane-pyridine, borane-THF, lithium aluminum hydride, lithiumdi-(sec)butyl borohydride, etc) followed by hydrolysis with dilutehydrogen chloride in methanol at a temperature between 0 and 140° C.,preferably around 50° C., for 4-24 hr, preferably about 14 hr, provideseither sulfonamide F or amine G.

Cyclic amines (compound II) from Scheme 1 which are spirocyclicpiperidines are prepared using azacyclic starting materials preparedusing methods described in the literature; more specifically, asdescribed in Claremon, D. A. et al, European Patent Publication 0 431943, Evans, B.E. et al, U.S. Pat. No. 5,091,387, Davis, L. et al U.S.Pat. No. 4,420,485, and Parham et al, Journal of Organic Chemistry, 41,2628 (1976). None of the compounds in the foregoing references arealleged to be chemokine receptor modulators.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

EXAMPLE 1

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine

Step 1

4-(4-Fluorophenyl)piperidine

A mixture of 10 g (47 mmol) of 4-(4-fluorophenyl) tetrahydro pyridinehydrochloride (Aldrich-Saylor) and 1.18 g of 10% Pd/C in 100 mL ofdegassed MeOH (N₂) was stirred under hydrogen at 45 psi for 18 h. Thereaction mixture was then filtered though a thin pad of celite elutingwith MeOH. The filtrate was concentrated and the residue was stirred in75 mL of ether. To it at 0° C. was added 5 g of solid NaOH. The layerswere separated and the aqueous layer was extracted with ether. Thecombined organic fractions were washed with sated NaCl solution, driedover Na₂SO₄, filtered and the filtrate was concentrated. The residue wascrystalized from cold heptane to give 10 g of the title compound.

Step 2

Ethyl4-(4-(4-fluorophenyl)piperidinyl)fumarate

A solution of 2.87 g (20 mmol) of mono-ethylfumarate (Aldrich), 3.24 g(20 mmol of 4(4-fluorophenyl)piperidine, 2.93 g (24 mmol) of4-dimethylaminopyridine, and 7.67 g (40 mmol) of1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in 40 mLof CH₂Cl₂ at rt was stirred for 2.5 h. The reaction mixture was dilutedwith CH₂Cl₂, washed with NaHCO₃, dried over Na₂SO₄, filtered. Thefiltrate was concentrated and the residue was purified by chromatography(silica, acetone:hexanes, 1:3) to give 4.4 g of the title compound. ¹HNMR (CDCl₃) δ7.44 (d, 1H, J=15.5 Hz), 7.14-7.16 (m, 2H), 7.00 (t, 2H,J=8.5 Hz), 6.77 (d, 1H, J=15.5 Hz), 4.26 (q, 2H, J=7 Hz), 1.33 (t, 3H,J=7 Hz).

Step 2

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine

To a solution of 4.4 g (14.4 mmol) ofethyl-4-(4-(4-fluorophenyl)piperidinyl)fumarate, and 4.1 g (17.3 mmol)of N-(methoxymethyl)-N-trimethylsilyl methyl)benzylamine in 30 mL ofCH₂Cl₂ at 0° C. was added 0.55 mL (7.2 mmol) of trifluoroacetic acid andthe reaction mixture was stirred at 0° C. for 1 h. The reaction mixturewas diluted with CH₂Cl₂ and washed with sat'd NaHCO₃. The combinedorganic fraction was dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chomatography (silica,acetone:hexanes, 1:3) to give 6.4 g of the title compound. ¹H NMR(CDCl₃) δ7.32-7.33 (m, 4H), 7.24-7.28 (m, 1H), 7.12-7.16 (m, 2H), 7.00(t, 2H, J=8.2Hz), 4.81 (d, 1H, J=13 Hz), 4.11-4.19 (m, 3H), 3.59-3.77(m, 4H), 3.03-3.18 (m, 3H), 2.86 (t, 1H, J=8.0 Hz), 2.50-2.77 (m, 4H),1.88-1.90 (m, 2H), 1.44-1.65 (m, 2H), 1.26 (t, 3H, J=7.0 Hz), ompleteNMR, Spectrum (ESI) m/e=439 (M+1).

EXAMPLE 2

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidine

To a solution of 6.4 g (14.6 mmol) of1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidinein 60 mL of THF at 0° C. was added 17.5 mL (17.5 mmol) of a 1M solutionof lithium aluminum hydride (LAH) in ether and the reaction was stirredat 0° C. for 30 min. The reaction mixture was quenched with SN NaOH. Thereaction mixture was extracted with ether and the combined organicfractions were washed with 5N NaOH solution. The organic fractions weredried over Na₂SO₄, filtered and the filtrate was purified bychromatography [silica, hexanes:ethyl acetate:(2N NH₃ in MeOH), 10:10:1]to give 4.7 g of the title compound. Spectrum (ESI) m/e=383 (M+1). ¹HNMR (CDCl₃) δc7.31-7.33 (m, 4 H), 7.26-7.28 (m, 1H), 7.16-7.19 (m, 2H),6.97 (t, 2H, J=8.5 Hz), 3.63-3.66 (m, 2H), 3.57 (d, 1H, J=13Hz), 3.43(t, 1H, J=10 Hz), 3.22 (d, 1H, J=11 Hz),2.97 (d, 1H, J=11 Hz), 2.80 (dof d, 1H, J=8.5, 7.5 Hz), 2.76 (t, 1H, J=9 Hz), 2.12-2.54 (m, 8 H), 2.02(t of d, 1H, J=2.5, 12 Hz), 1.75-1.85 (m, 5H).

EXAMPLE 3

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidine

Step 1

3-(RS)-(4-(4-Fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidine

A mixture of 0.89 g (2.3 mmol) of1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidine,2.9 g (17.7 mmol) of ammonium formate and 0.39 g of Pearlman's catalyst[Pd(OH)₂/C] in 30 mL of MeOH was stirred at 70° C. for 1 h. The reactionmixture was filtered through a thin pad of Celite and the filtrate wasconcentrated to give 0.7 g of the title compound.

Step 2

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinyl-methyl)-164-(SR)-hydroxyethylpyrrolidine

To a solution of 0.63 g (2.15 mmol) of3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidineand 0.6 mL (4.3 mmol) of Et₃N in 20 mL of CH₂Cl₂ at 0° C. was added 0.32mL (2.15 mmol) of 2-naphthoyl chloride and the reaction mixture wasstirred for 1.2 h. To the reaction mixture was added 0.5 mL of MeOH andthe reaction mixture was stirred 18 h at rt. The reaction mixture wasconcentrated and the residue was purified by chomatography (silica,acetone:hexanes, 1:2 to 1:1) to give 0.63 g of the title compound. ¹HNMR (CDCl₃) δ7.85-7.91 (m, 3H), 7.45-7.58 (m, 4H), 7.14-7.20 (m, 2 H),6.96-7.00 (m, 2H); Mass Spectrum (ESI) m/e=447 (M+1).

EXAMPLE 4

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine

To a solution of 0.1 mL (1.2 mmol) of oxalyl chloride in 10 mL of CH₂Cl₂at −78° C. was added 0.17 mL (2.37 mmol) of DMSO and the reactionmixture was stirred for 10 min. To this reaction mixture at −78° C. wasadded a solution of 0.26 g (0.59 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidinein 10 mL of CH₂Cl₂. After stirring for 10 min. at −78° C., 0.41 mL (2.9mmol) of Et₃N was added and the reaction was allowed to warm to rt. Thereaction mixture was poured into ether and washed twice with sat'dNaHCO₃ solution and once with sat'd NaCl solution. The organic fractionwas dried over NaSO₄, filtered and the filtrate was concentrated to give0.29 g of the title compound. ¹H NMR (CDCl₃) δ9.85, 9.70 (d, 1H, J=2.0Hz),7.86-7.91 (m, 2H), 7.48-7.55 (m, 3H), 7.10-7.18 (m, 2H), 6.94-7.00(m, 2H); Mass Spectrum (ESI) m/e=445 (M+1).

EXAMPLE 5

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(1-morpholinomethyl)pyrrolidine

To a solution of 0.03 g (0.073 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidineand 0.013 mL (0.145 mmol) of morpholine in 2 mL of dichloroethane at rtwas added 0.046 g (0.27 mmol) of sodium triacetoxyborohydride. Afterstirring for 1.5 h at rt, the reaction mixture was partitioned betweenCH₂Cl₂ and sat'd NaHCO₃. The organic fraction was dried over Na₂SO₄,filtered and the filtrate was concentrated. The residue was purified bychomatography (silica, CH₂Cl₂:MeOH, 95:5) to give the title compound. 1HNMR (CDCl₃) δ (complete) 7.87-7.90 (m, 3H), 7.45-7.55 (m, 4H),7.17-7.20, 7.08-7.11 (m, 2H), 7.00, 6.95 (t, 2H, J=9.0 Hz),4.03-4.09 (m,1H), 3.72 (t, 2H, <J=4.5 Hz), 3.60-3.64 (m, 1H), 3.56 (t, 2H, J=4.5 Hz),2.97-3.06 (m, 2H), 2.82-2.88 (m, 1H), 2.43-2.55 (m, 4H), 2.24-2.43 (m,5H), 2.09-2.19 (m, 3H), 1.49-1.98 (m, 5H); Mass Spectrum (ESI) m/e=516(M+1).

EXAMPLE 6

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(ethylaminomethyl)pyrrolidine

The title compound was prepared as described in Example 5. Mass Spectrum(ESI) m/e=474 (M+1).

EXAMPLE 7

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)4-(RS)-(benzylaminomethyl)pyrrolidine

The title compound was prepared as described in Example 5. Mass Spectrum(ESI) m/e=536 (M+1).

EXAMPLE 8

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine

A mixture of 0.126 g (0.28 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidine, 0.18 g (0.85 mmol) of NaIO₄, and 0.0029 g (0.014 mmol) ofRuCl₃.3 H₂O in 2 mL of CCl₄, 3 mL of H₂O and 2 mL of CH₃CN was stirredat rt for 1 h. The reaction mixture was partitioned between CH₂Cl₂ andH₂O. The organic fraction was dried over Na₂SO₄, filtered and thefiltrate was concentrated to give the title compound. ¹H NMR (key peaks)(CDCl₃) δ7.81-7.88 (m, 3H), 7.43-7.74 (m, 4H), 7.11-7.14 tm, 2H), 6.97(t, 2H, J=8.0 Hz), Mass Spectrum (ESI) m/e=461 (M+1).

EXAMPLE 9

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-methoxycarbonylpyrrolidine

To a solution of 0.037 g (0.08 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidinein 0.6 mL of MeOH and 1.2 mL of THF at rt was added 0.2 mL (0.4 mmol) ofTMSCHN₂ (2M in hexanes) and the reaction mixture was stirred for 6 h.The reaction mixture was concentrated and the residue was purified bychromatography (silica, acetone:hexanes, 1:3) to give the titlecompound. ¹H NMR (CDCl₃) δ (key peaks) 7.87-7.91 (m, 3H), 7.47-7.56 (m,4H), 7.15-7.18 and 7.08-7.11 (m, 2H), 6.98 and 6.95 (t, 2H, J=8.5Hz),3.79 and 3.62 (s, 3H1); Mass Spectrum (ESI) m/e=475 (M+1).

EXAMPLE 10

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-ethoxycarbonylpyrrolidine

To a solution of 0.026 g (0.057 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine,0.03 g (0.114 mmol) of BOP-Cl and 0.032 mL (0.228 mmol) of Et₃N in 2 mLof CH₂Cl₂ at rt was added 0.013 mL (0.228 mmol) of EtOH and the reactionmixture was stirred for 2 h. The reaction mixture was concentrated andthe residue purified by chromatography (silica, acetone:hexanes, 1:2)then by HPLC (silica, Waters RCM 25×100 with (0.1% iPr2NH in methyltbutyl ether):hexane=4.5:5.0 to give the title compound. ¹H NMR (CDIC₃)δ (key peaks) 7.88-7.91 (m, 3H), 7.47-7.57 (m, 4H), 7.16-7.19 and7.09-7.12 (m, 2H), 6.99 and 6.96 (t, 2H, J=8.5 Hz),1.34 and 1.21 (t, 3H,J=7.0 Hz); Mass Spectrum (ESI) m/e=489 (M+1).

EXAMPLE 11

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-isopropyloxycarbonylpyrrolidine

The title compound was prepared as described in Example 10. MassSpectrum (ESI) m/e=503 (M+1).

EXAMPLE 12

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-benzyloxycarbonylpyrrolidine

The title compound was prepared as described in Example 10. ¹H NMR(CDCl₃) δ (key peaks) 7.88-7.91 (m, 3H), 7.45-7.56 (m, 3H), 7.27-7.41(m, 5H), 7.08-7.16 (m, 2H), 6.99 and 6.96 (t, 2H, J=9.0 Hz), 5.26 and5.12 (d, 1H, J=12.5 Hz), 5.22 and 5.06 (d, 1H, J=12.5 Hz); Mass Spectrum(ESI) m/e=551 (M+1).

EXAMPLE 13

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N-ethylaminocarbonyl)pyrrolidine

To a solution of 0.037 g (0.08 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidineand 0.06 mL (0.12 mmol) of ethylamine in 2 mL of CH₂Cl₂ at rt was added0.031 g (0.12 mmol) of BOPCl Bis(2-oxo-3-oxazolidinyl)phosphinicchloride, Aldrich) and 0.045 mL Et₃N and the reaction mixture wasstirred for 18 h. The reAction mixture was concentrated and the residuewas purified by chromatography (silica, acetone:hexanes, 1:2) to givethe title compound. 1H NMR (CDCl₃) δ (key peaks) 7.85-7.90 (m, 3H),7.45-7.56 (m, 4H), 7.09-7.19 (m, 2H), 6.96-7.03 (m, 2H), 3.94-4.49 (m,4H); Mass Spectrum (ESI) m/e=488 (M+1).

EXAMPLE 14

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N,N-diethylaminocarbonyl)pyrrolidine

The title compound was prepared as described in Example 13. MassSpectrum (ESI) m/e=516 (M+1).

EXAMPLE 15

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(phenoxymethyl)pyrrolidine

A solution of 0.062 g (0.14 mmol) of Ph₃Bi (Aldrich) in 1 mL of CH₂Cl₂and 0.65 mL of THF at rt was added 0.027 mL (0.18 mmol) oftrifluoroacetic acid and the reaction mixture was stirred for 10 min.This solution was added to a solution of 0.046 g (0.1 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidinein 1 mL of CH₂Cl₂. To this reaction mixture was added 0.0083 g (0.046mmol) of Cu(OAc)₂ and the reaction mixture was stirred at 40° C. for 72h. The reaction mixture was filtered through a thin pad of silica(acetone:hexanes, 1:2) and the filtrate was concentrated. The residuewas purified by chromatography (silica, Waters RCM 25×100 with (0.1%iPr₂NH in methyl tbutyl ether):hexane=2.25:7.0) to give the titlecompound. ¹H NMR (CDCl₃) δ (key peaks) 7.88-7.92 (m, 3H), 7.47-7.56 (m,4H), 7.23-7.34 (m, 2H), 7.07-7.18 (m, 2H), 6,92-7.01 (m, 4H), 6.80 (d,1H, J=7.5 Hz), 5.12 (S, 2H). Mass Spectrum (ESI) m/e=523 (M+1).

EXAMPLE 16

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S,R)-(ethoxymethyl)pyrrolidine

To a solution of 0.033 g (0.074 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidineand 0.057 g (0.22 mmol) of AgOTf in 2 mL of CH₂Cl₂ was added 0.058 mL(0.26 mmol) of 2,6-di-t-butylpyridine and 0.019 mL (0.24 mmol) of ethyliodide and the reaction mixture was stirred at rt for 1.5 h. Thereaction mixture was diluted with CH₂Cl₂ and filtered through a thin padof Celite eluting with acetone:hexanes (1:2). The filtrate wasconcentrated and the residue was purified by chromatography (silica,acetone:hexanes, 1:3 to 1:2) to give the title compound. ¹H NMR (CDCl₃)δ (key peaks) 7.88-7.91 (M, 3H), 7.47-7.57 (M, 4H), 7.09-7.12 and7.18-7.21 (M, 2H, 7.01 and 6.96 (t, 2H, J=8.5 Hz), 1.25 and 1.09 (t, 3H,J=7.0 Hz); Mass Spectrum (ESI) m/e=475 (M+1).

EXAMPLE 17

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(methoxymethyl)pyrrolidine

A solution of 0.025 g (0.057 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidine,0.013 g (0.23 mmol) of KOH and 0.028 mL (0.46 mmol) of methyl iodide in2 mL of DMSO was stirred at rt for 1.2 h. The reaction mixture waspoured into ether and washed with sat'd NaHCO₃ and NaCl solutions, driedover Na₂SO₄ and filtered. The filtrate was concentrated and the residuewas purified by chromatography (silica, acetone:hexanes, 1:2) to givethe title compound. Mass Spectrum (ESI) m/e=461 (M+1).

EXAMPLE 18

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine(diastereomers 1 and 2)

To a solution of 0.03 g (0.67 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidinein 6 mL of THF at 0° C. was added 1.34 mL (1.34 mmol) of MeMgBr (1M inTHF). The reaction mixture was warmed to rt and stirred for 3 h. Thereaction mixture was quenched with sat'd NaHCO₃ solution. The organicfraction was filtered through a thin pad of Celite. The filtrate wasconcentrated and purified by chromatography (silica, hexanes:ethylacetate:EtOH, 10:10:1) to give 0.05 g of diastereomer #1 and 0.16 g ofdiastereomer #2.

Diastereomer #1

¹H NMR (CDCl₃) δ (key peaks) 7.86-7.91 (m, 3H), 7.46-7.58 (m, 4H),7.13-7.19 (m, 2H), 6.94-7.00 (m, 2H), 1.30 and 0.90 (d, 3H, J=6.0 Hz);Mass Spectrum (ESI) m/e=461 (M+1).

Diastereomer #2

¹H NMR (CDCl₃) δ (key peaks) 7.84-7.90 (m, 3H), 7.44-7.56(m, 4H),7.12-7.18 (m, 2H), 6.94-6.98 (m, 2H), 1.24 and 1.03 (d, 3H, J=6.5 Hz)Mass Spectrum (ESI) m/e=461 (M+1).

The following Examples 19 to 24 were prepared from1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidineand the corresponding Grignard reagent as described in Example 19.

EXAMPLE 19

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxypropyl)pyrrolidine

Diastereomer #1

Mass Spectrum (ESI) m/e=475 (M+1).

Diastereomer #2

Mass Spectrum (ESI) m/e=475 (M+1).

EXAMPLE 20

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxy-2-propenyl)pyrrolidine

Diastereomer #1

Mass Spectrum (ESI) m/e=473 (M+1).

Diastereomer #2

Mass Spectrum (ESI) m/e=473 (M+1).

EXAMPLE 21

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxy-2-propynyl)pyrrolidine

Mass Spectrum (ESI) m/e=471 (M+1).

EXAMPLE 22

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxy-3-butenyl)pyrrolidine

Diastereomer #1

Mass Spectrum (ESI) m/e=487 (M+1).

Diastereomer #2

Mass Spectrum (ESI) m/e=487 (M+1).

EXAMPLE 23

1-(-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(phenylhydroxymethyl)pyrrolidine

Diastereomer #1

Mass Spectrum (ESI) m/e=523 (M+1).

Diastereomer #2

Mass Spectrum (ESI) m/e=523 (M+1).

EXAMPLE 24

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4)-SR)-(2-phenyl-1-hydroxyethyl)pyrrolidine

Mass Spectrum (ESI) m/e=537 (M+1).

EXAMPLE 25

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-acetoxyethyl)pyrrolidine

A solution of 0.026 g (0.057 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine(diastereomer 2, Example 18), 0.027 mL (0.28 mmol) of acetic anhydride,0.046 mL of pyridine and 3.4 mg of DMAP in 2 mL of THF was stirred at rtfor 18 h. The reaction mixture was concentrated and purified bychromatography (silica, hexanes:ethylacetate:(2N NH₃ in MeOH), 15:15:1)to give the title compound as white solid. ¹H NMR (CDCl₃) δ (key peaks)7.89-7.90 (m, 3H), 7.47-7.54 (m, 4H), 7.19 and 7.09 (d of d, 2H, J=6.0,8.5 Hz), 6.99 and 6.94 (t, 2H, J=8.5 Hz), 5.04-5.20 (m, 1H1), 1.34 and1.09 (d, 3H, J=6.5 Hz), Mass Spectrum (ESI) m/e=503 (M+1).

EXAMPLE 26

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-methoxyethyl)pyrrolidine

A solution of 0.026 g (0.057 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidine(diastereomer 2), 0.012 mg (0.23 mmol) of KOH and 0.0042 mL (0.068 mmol)of methyliodide in 1 mL of DMSO was stirred at rt for 30 min. Thereaction mixture was diluted with ether and washed with sat'd NaHCO₃ andNaCl solutions. The organic fraction was dried over Na₂SO₄, filtered andthe filtrate was concentrated and purified by chromatography (silica,hexanes:ethylacetate:(2N NH₃ in MeOH), 10:10:1) to give the titlecompound. ¹H NMR (CDCl₃) δ (key peaks) 7.88-7.91(m, 3H), 7.45-7.55 (m,4H), 7.20 and 7.10 (d of d, 2H, J=5.5, 8.5 Hz), 7.00 and 6.95 (t, 2H,J=9.0 Hz), 3.40 and 3.24 (s, 3H) 1.25 and 1.02 (d, 3H, J=6.5 Hz), MassSpectrum (ESI) m/e=475 (M+1).

EXAMPLE 27

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-acetylpyrrolidine

The title compound was prepared from1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxyethyl)pyrrolidineaccording to procedures described in Example 4. ¹H NMR (CDCl₃) δ (keypeaks) 7.86-7.91 (m, 3H), 7.44-7.57 (m, 4H), 7.08-7.16 (m, 2H),6.93-6.99 (m, 2H), 2.34 and 2.17 (s, 3H); Mass Spectrum (ESI) m/e=459(M+1).

EXAMPLE 28

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-benzoylpyrrolidine

The title compound was prepared from1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(phenylhydroxymethyl)pyrrolidine according to procedures described in Example 4. ¹H NMR(CDCl₃) δ (key peaks) 8.14 (d, 1H, J=7.5 Hz), 7.97-8.01 (m, 2H),7.42-7.63 (7H), 6.93-7.01 (m, 4H), Mass Spectrum (ESI) m/e=521 (M+1).

EXAMPLE 29

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1-hydroxy-1-methylethyl)pyrrolidine

To a solution of 0.03 g (0.065 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-acetylpyrrolidinein 20 mL of THF at rt was added 0.19 mL (0.195 mmol) of MeMgBr (1M inTHF) and the reaction mixture was stirred for 30 min. The reactionmixture was partitioned between CH₂Cl₂ and NaHCO₃. The organic fractionwas filtered through a thin pad of Celite and the filtrate wasconcentrated. The residue was purified by chromatography (silica,MeOH:CH₂Cl₂, 2:98) to give the title compound. ¹H NMR (CDCl₃) δ (keypeaks) 7.88-7.89 (m, 3H), 7.45-7.57 (m, 4H), 7.13-7.19 (m, 2H),6.94-6.99 (m, 2H), 1.31 and 1.08 (s, 3H), 1.25 and 0.91 (s, 3H); MassSpectrum (ESI) m/e=475 (M+1).

EXAMPLE 30

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N-ethylcarbamoyloxymethyl)pyrrolidine

Step 1

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinyl-methyl)-4-(SR)-(4-nitrophenoxycarbonyloxymethyl)-pyrrolidine

A solution of 0.1 g (0.225 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)4-(nitrophenoxycarbonyloxymethyl)pyrrolidine, 0.055 g (0.45 mmol) of DMAP, 0.094 mL (0.68 mmol)of Et₃N and 0.082 g (0.41 mmol) of 4-nitrophenylchloroformate in 4 mL ofCH₂Cl₂ was stirred at rt for 16 h. The reaction mixture was concentratedand the title compound was used without further purfication.

Step 2

A solution of 0.045 g (0.075 mmol) of1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N-ethylcarbamoyloxymethyl)pyrrolidine and 0.23 mL (0.45 mmol) of ethylamine in 2 mL ofCH₂Cl₂ was stirred at rt for 2 h. The reaction mixture was diluted withether and washed twice with 2N NaOH solution. The organic fraction wasdried over Na₂SO₄, filtered and the filtrate was concentrated. Theresidue was purified by chromatography (silica, acetone:hexanes, 1:3) togive the title compound. ¹H NMR (CDCl₃) δ (key peaks) 7.85-7.91 (m, 3H),7.45-7.56 (m, 4H), 7.08-7.20 (m, 2H), 6.93-7.01 (m, 2H), 1.17 (t, 3H,J=7.0 hz); Mass Spectrum (ESI) m/e=518 (M+1).

EXAMPLE 31

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N,N-diethylcarbamoyloxymethyl)pyrrolidine

The title compound was prepared as described in Example 30, usingdiethylamine. Mass Spectrum (ESI) m/e=546 (M+1).

EXAMPLE 32

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine

Step 1

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine

The title compound was prepared from1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethylpyrrolidineaccording to procedures described in Example 4.

Step 2

1-(Benzyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine

A solution of 0.046 g (0.104 mmol) of1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine,0.058 mL (1.04 mmol) of ethyleneglycol and 0.047 g (0.25 mmol) ofTsOH.H₂O in 5 mL of benzene was heated at reflux for 2 h. The reactionmixture was cooled to rt and diluted with ether. The reaction mixturewas washed twice with sat'd NaHCO₃ solution, dried over Na₂SO₄, filteredand the filtrate was concentrated. The residue was purified bychromatography (silica, MeOH:CH₂Cl₂, 5:95) to give the title compound.

Step 3

3-(RS)-(4-(4-Fluorophenyl)piperidinylmethyl)-4-(SR)-((1,3-dioxolan-2-yl)pyrrolidine

The title compound was prepared as described in Example 3, Step 1.

Step 4

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine

The title compound was prepared from3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S,R)-(1,3-dioxolan-2-yl)pyrrolidineand 2-naphthoylchloride as described in Example 3, Step 2. ¹H NMR(CDCl₃) δ (key peaks) 7.87-7.93 (m, 3H), 7.46-7.55 (m, 4H), 7.19 and7.09 (d of d, 2H, J=5.5, 8.5 Hz), 7.00 and 6.95 (t, 2H, J=8.5 Hz), 5.03and 4.85 (d, 1H, J=3.5 Hz); Mass Spectrum (ESI) m/e=489 (M+1).

The following Examples 34 to 36 were prepared from1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidineand the corresponding diol according to procedures described in Example33.

EXAMPLE 34

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-methyl-1,3-flouromethyl-1,3-dioxolan-2yl)pyrrolidine

Mass Spectrum (ESI) m/e=504 (M+1).

EXAMPLE 35

1-(2-Naphthoyl)-3-(RS)-(4-(4fluorophenyl)piperidinylmethyl)-4-(SR)-(4-flouromethyl-1,3-dioxolan-2-yl)pyrrolidine

Mass Spectrum (ESI) m/e=522 (M+1).

EXAMPLE 35

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-methoxymethyl-1,3-dioxolan-2-yl)pyrrolidine

Mass Spectrum (ESI) m/e=534 (M+1).

EXAMPLE 36

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxan-2-yl)pyrrolidine

Mass Spectrum (ESI) m/e=503 (M+1).

EXAMPLE 37

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S,R)-(1,1-dimethoxymethyl)pyrrolidine

A solution of 0.035 g (0.078 mmol) of1-(2-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(SR)-formylpyrrolidine,0.085 mL (0.78 mmol) of trimethylorthoformate and 0.018 g (0.094 mmol)of TsOH.H₂O in 2 mL of MeOH was heated at reflux for 2 h. The reactionmixture was diluted with ether and washed twice with sat'd NaHCO₃solution and NaCl solution. The organic fraction was dried over Na₂SO₄,filtered and the filtrate was concentrated. The residue was purified bychromatography [silica, ethyl acetate:hexanes:(2N NH₃ in MeOH), 10:10:1]to give the title compound. ¹H NMR (CDCl₃) δ (key peaks) 7.87-7.91 (m,3H), 7.45-7.55 (m, 4H), 7.19 and 7.09 (d of d, 2H, J=5.5, 9.0 Hz), 7.00and 6.95 (t, 2H, J=8.5 Hz), 4.38 and 4.27 (d, 1H, J=6.0 Hz); MassSpectrum (ESI) m/e=491 (M+1).

EXAMPLE 38

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(SR)-(1,1-diethoxymethyl)pyrrolidine

The title compound was prepared as described in Example 39 usingtriethylorthoformate. Mass Spectrum (ESI) m/e=519 (M+1).

EXAMPLE 40

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

Step 1

1-Benzyl-3-(RS)-carboethoxy-4-(RS)-trifluoromethylpyrrolidine

The title compound (1.8 g) was prepared from ethyl-3-trifluoromethylacrylate, and N-(methoxymethyl)-N-trimethylsilyl methyl)benzylamine asdescribed in Example 1, Step 2. ¹H NMR (CDCl₃) δ (complete) 7.27-7.42(m, 5H), 4.20 (q, 2H, J=7.0 Hz), 3.67 (d, 1H, J=13 Hz), 3.61 (d, 1H,J=13 Hz), 3.37-3.43 (m, 3.12-3.15 (m, 1H), 2.81-2.93 (m, 3H), 2.71 (d ofd, 1H, J=6, 10 Hz).

Step 2

1Benzyl-3-(RS)-hydroxymethyl4-(RS)-trifluoromethyl pyrrolidine

To a solution of 1.8 g (6 mmol) of1-benzyl-3-(RS)-carboethoxy-4-(RS)-trifluoromethylpyrrolidine in 20 mLof THF at 0° C. was added 4.8 mL (4.8 mmol) of a 1M solution of LAH inTHF and the reaction was stirred at rt for 30 min. The reaction mixturewas quenched with 5N NaOH solution and extracted with ether. Thecombined organic fractions were washed with 2N NaOH solution and sat'dNaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chromatography (silica,acetone:hexanes, 1:8) to give 1.5 g of the title compound. ¹H NMR(CDCl₃) δ (key peaks) 7.28-7.37 (m, 5H), 3.76 (d of d, 1H, J=3.5, 10.5Hz), 3.63 (s, 2H), 3.62 (d of d, 1H, J=5.0, 10.5 Hz), 3.11 (t, 1H, J=9.0Hz), 2.60 (t, 1H, J=7.0 Hz), 2.45-2.49 (m, 1H), 2.42 (d of d, 1H, J=7.5,9.5 Hz).

Step 3

1-Benzyl-3-(RS)-formyl-4-(RS)-trifluoromethylpyrrolidine

To a solution of 0.98 mL (11.2 mmol) of oxalyl chloride in 30 mL ofCH₂Cl₂ at −78° C. was added 1.6 mL (22.4 mmol) of DMSO and the reactionmixture was stirred for 10 min. To this reaction mixture at −78° C. wasadded a solution of 1.46 g (5.6 mmol) of1-benzyl-3-(RS)-hydroxymethyl-4-(RS)-trifluoromethylpyrrolidine in 10 mLof CH₂Cl₂. After stirring for 10 min. at −78° C., 3.9 mL (28 mmol) ofEt₃N was added and the reaction was allowed to warm to rt. The reactionmixture was poured into ether and extracted twice with sat'd NaHCO₃solution and once with sat'd NaCl solution. The organic fraction wasdried over Na₂SO₄, filtered and the filtrate was concentrated to give1.46 g of the title compound.

Step 4

1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

To a solution of 1.46 g (5.6 mmol) of1-benzyl-3-(RS)-formyl-4-(RS)-trifluoromethylpyrrolidine and 0.13 g(0.67 mmol) of 4-(4-fluorophenyl) piperidine (Example 1, Step 1) in 30mL of dichloroethane at rt was added 2.37 g (11.2 mmol) of sodiumtriacetoxyborohydride. After stirring for 18 h at rt, the reactionmixture was partitioned between CH₂Cl₂ and sat'd NaHCO₃. The organicfraction was dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chomatography (silica,acetone:hexanes, 1:8) to give 1.98 g of the title compound. ¹H NMR (keypeaks) (CDCl₃) δ7.28-7.37 (m, 5H), 7.19-7.22 (m, 2H), 7.01 (t, 2H, J=8.5Hz); Mass Spectrum (ESI) m/e=421 (M+1).

EXAMPLE 41

1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

Step 1

3-(RS)-(4-(4-Fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidine

The title compound was prepared from1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidineaccording to procedures described in Example 3.

Step 2

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

The title compound was prepared from3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidineaccording to procedures described in Example 3, Step 2. ¹H NMR (keypeaks) (CDCl₃) d 7.17-7.20 (m, 2H), 6.99 (t, 2H, J=8.5 Hz), MassSpectrum (ESI) m/e=331 (M+1).

EXAMPLE 42

1-(7-Indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

A solution of 0.12 g (0.36 mmol) of3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidine,0.069 g (0.43 mmol) of indole-7-carboxylic acid, 0.088 g (0.72 mmol) ofDMAP and 0.097 g (0.5 mmol) of1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich)in 10 mL of CH₂Cl₂ was stirred at rt for 4 h. The reaction mixture wasconcentrated and the residue was purified by chromatography (silica,acetone:hexanes, 1:5) to give the title compound. 1H NMR (key peaks)(CDCl₃) δ9.96 (s, 1H), 7.82 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.5 Hz),7.32 (t, 1H, J=3.0 Hz), 7.17-7.21 (m, 3H), 7.03 (t, t, 2H, J=8.5 Hz),6.62-6.63 (m, 1H); Mass Spectrum (ESI) m/e=474 (M+1).

EXAMPLE 43

1-(1-Methyl-7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

To a solution of 0.033 g (0.07 mmol) of1-(7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidineand 0.022 g (0.084 mmol) of 18-Crown-6 ether in 2 mL of ether at rt wasadded 0.084 mL of KOt-Bu (1M in t-BuOH). After stirring for 5 min, 0.006mL (0.098 mmol) of MeI was added and the reaction was stirred for 1 h.The reaction mixture was concentrated and the residue was purified bychromatography (silica, acetone:hexanes, 1:3) to give the titlecompound. ¹H NMR (CDCl₃) δ (key peaks) 7.68-7.70 (m, 1H), 7.10-7.21 (m,4H), 7.06 (t, 1H, J=3.0 Hz), 6.97-7.03 (m, 2H), 6.55 (d, 1H, J=3.0 hz);Mass Spectrum (ESI) m/e 488 (M+1).

EXAMPLE 44

1-(1-t-Butoxycarbonylmethyl)-7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

The title compound was prepared as described in Example 40 usingt-butylbromoacetate. Mass Spectrum (ESI) m/e=588 (M+1).

EXAMPLE 45

1-(1-Carboxymethyl)-7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidine

A solution of 0.036 g of1-(1-t-butoxycarbonylmethyl)-7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(trifluoromethyl)pyrrolidineand 0.05 mL of H₂O in 2 mL of TFA was stirred at rt for 40 min. Thereaction mixture was concentrated and the residue was purified bychromatography (silica, CH₂Cl₂, MeOH, NH₃, 100:10:3) to give the titlecompound. Mass Spectrum (ESI) m/e=532 (M+1).

EXAMPLE 46

1-(1-Methyl-7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(phenylhydroxymethyl)pyrrolidine(Diastereomers 1 and 2)

Step 1

1-Benzyl-3-(RS)-(4(4fluorophenyl)piperidinylmethyl)-4-(SR)-(phenylhydroxymethyl)pyrrolidine

The title compound was prepared from1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidineaccording to procedures described in Example 18.

Step 2

3-(RS)-(4-(4-Fluorophenyl)piperidinylmethyl)-4-(RS)-(phenylhydroxymethyl)pyrrolidine

The title compound was prepared from1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(phenylhydroxymethyl)pyrrolidineas described in Example 3.

Step 3

1-Methylindole-7-carboxylic Acid

Step 3A

Benzylindole-7-carboxylate

A solution of 0.68 g (4.2 mmol) of indole-7-carboxylic acid, 0.9 g (8.4mmol) of benzylalcohol 1.03 g (8.4 mmol) of DMAP and 1.6 g (8.4 mmol) of1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich)in 30 mL of CH₂Cl₂ was stirred at rt for 18 h. The reaction mixture wasconcentrated and the residue was purified by chromatography (silica,hexanes:ethyl acetate 30:1) to give 0.88 g of the title compound.

Step 3B

Benzyl-1-methyl-7-indolecarboxylate

The title compound (0.15 g) was prepared from benzyl-7-indolecarboxylateaccording to procedures described in Example 40.

Step 3C

1-Methyl-7-indolecarboxylic Acid

The title compound (0.102 g) was prepared frombenzyl-1-methyl-7-indolecarboxylate according to procedures described inExample 3.

Step 4

1-(1-Methyl-7-indolecarbonyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(phenylhydroxymethyl)pyrrolidine

The title compound was prepared from3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(phenylhydroxymethyl)pyrrolidineand 1-methyl-7-indolecarboxylic acid according to procedures describedin Example 39. The crude product was purified by chromatography (silica,acetone:hexane=1:2) to give the separate diastereomers of the titlecompound.

Diastereomer #1

Mass Spectrum (ESI) m/e=526 (M+1).

Diastereomer #2

Mass Spectrum (ESI) m/e=526 (M+1).

EXAMPLE 47

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(t-butyl)pyrrolidine

Step 1

Methyl-3-t-butylacrylate

To a solution of 22.8 g (125 mmol) of trimethylphosphonoacetate in 25 mLof THF at −20° C. was added 125 mL (125 mmol) of a solution of sodiumbis(trimethylsilyl)amide (1 M) in THF. After stirring for 20 min, 7.7 g(aoo mmol) of trimethylacwetaldehyde and the reaction mixture wasstirred at −20° C. for 2 h. The reaction mixture was partitioned betweenH₂O and ether. The organic fractrion was washed with H₂O, and sat'd NaClsolution, dried over MgSO₄, and filtered. The filtrate was concentratedto give the title compound which was used without further purification.

Step 2

N-allyl-N-(trimethylsilylmethyl)amine

To 118 mL (1.57 mol) of allylamine warmed at 40° C. in an inertatmosphere was very slowly added 100 mL (0.72 mol) of chloromethyltrimethylsilane (approximate rate of 1 mL/min). The reaction mixture wasslowly warmed to 70° C. and stirred for 24 h. The reaction mixture wascooled to 0° C. and to it was added water to break up the gel and then300 mL of 2N NaOH solution. The reaction mixture was extracted withether. The combined organic fractions were washed with 500 mL of sat'dNaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by distillation (bp 80-84° C. @100 torr) to give 75 g of the title compound.

Step 3

N-Allyl-N-(methoxymethyl)-N-trimethylsilylmethyl)amine

To 75 g (0.57 mol) of N-allyl-N-(trimethylsilylmethyl)amine at 0° C. wasslowly added 67 mL (0.88 mol) of aqueous formaldehyde (37% w/w). Afterstirring for 5 min, 65 mL (1.6 mol) of methanol was added followed bythe addition of 94 g (0.68 mol) of K₂CO₃. The reaction mixture waswarmed to rt and stirred for 12 h. The reaction mixture was partitionedbetween 300 mL of water and 300 mL of ether. The organic fraction waswashed with water and sat. NaCl solution. The combined aqueous fractionswere extracted with ether. The combined organic fractions were driedover Na₂SO₄, filtered and the filtrate was concentrated to give 89 g ofthe title compound which was used without further purification.

Step 4

1-Allyl-3-(SR)-carbomethoxy-4-(RS)-t-butylpyrrolidine

To a solution of 7.1 g (50 mmol) of methyl-3-t-butylacrylate, 18.7 g(100 mmol) of N-allyl-N-(methoxymethyl)-N-trimethyl silylmethyl)amine in150 mL of CH₂Cl₂ at 0° C. was added 0.8 mL (10 mmol) of trifluoroaceticacid and the reaction mixture was stirred for 4 h while warming to rt.The reaction mixture was diluted with sat'd NaHCO₃ and extracted twicewith 100 mL of ether. The combined organic fractions were washed withsat'd NaHCO₃ and NaCl solutions, dried over Na₂SO₄, filtered and thefiltrate was concentrated. The residue was filtered through a thin padof silica, eluting with acetone:hexanes (3:7) to give 6.7 g of the titlecompound.

Mass Spectrum (ESI) m/e=226 (M+1).

Step 5

1-Allyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidine

The title compound was prepared as described in Example 37. ¹H NMR(CDCl₃) δ7.19 (m,2H), 6.98 (t, 8.7 Hz, 2H), 5.94 (m, 1H), 5.21 (d of d,1.8 Hz, 7.2 Hz, 1H), 5.11 (d of d, 0.9 Hz, 10 Hz, 1H), 3.14 (m, 2H),2.97 (m, 2H), 2,79 (m, 2H), 2.48 (m, 2H), 2.29 (m, 2H), 2.22 (m, 1H),2.19-2.05 (m, 3H), 1.92 (m, 1H), 1.82-1.64 (m, 4H), 1.55 (m, 1H), 0.90(s, 9H); Mass Spectrum (ESI) m/e=359 (M+1).

Step 6

3-(SR)-(4-(4-Fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidine

A mixture of 1 g (2.7 mmol) of1-allyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidineand 0.13 g (0.14 mmol) of Wilkinson's catalyst [Rh(PPh₃)₃Cl] in 40 mL ofan 85% solution of CH₃CN and water was heated to 90° C. and stirred for3 h. The reaction mixture was cooled to rt and concentrated. The residuewas partitioned between EtOAc and water. The organic fraction was washedwith sat. NaHCO₃, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chomatography (silica, CHCl₃:MeOH:NH₃, 90:10:1) to give 0.75 g of the title compound.

Step 6

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinyl-methyl)-4-(RS)-(t-butyl)pyrrolidine

The title compound was prepared from3-(SR)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidineaccording to procedures described in Example 3, Step 2. ¹H NMR (CDCl₃)(key peaks) δ7.89 (m, 3H), 7.58-7.43 (m, 4H), 7.21, 7.08 (m,2H), 7.01,6.95 (m,2H), 0.82, 0.99 (s,9H):, Mass Spectrum (ESI) m/e=473 (M+1).

EXAMPLE 48

1-(3,4-Dichlorobenzoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(t-butyl)pyrrolidine

The title compound was prepared from3-(SR)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-t-butylpyrrolidineaccording to procedures described in Example 3, Step 2. Mass Spectrum(ESI) m/e=491 (M+1 35Cl, 35Cl) 493 (M+1 37Cl, 37Cl)

EXAMPLE 49

1(4-Chlorobenzyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(t-butyl)pyrrolidine

A solution of 0.025 g (0.08 mmol) of3-(SR)-(4-(4-fluoro)phenyl)piperidinylmethyl)-4(RS)-t-butylpyrrolidine,0.022 g (0.16 mmol) of 4-chlorobenzaldehyde and 0.043 g (0.2 mmol) ofsodium triacetoxy borohydride in 5 mL of 1,2-dichloroethane was stirredfor 2 h at rt. The reaction mixture was partitioned between ether andsat'd K₂CO₃ solution. The aqueous layer was extracted with ethyl acetateand the combined organic fractions were dried over Na₂SO₄, filtered andthe filtrate was concentrated. The residue was purified bychromatography (silica, acetone:hexanes, 1:3) to give the titlecompound. Mass Spectrum (ESI) m/e=457 (M+1 35Cl) 459 (M+1 37Cl).

EXAMPLE 50

1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

To a suspension of 0.08 g (0.22 mmol) of methyltriphenyl phosphoniumbromide (Ph₃PCH₃Br) in 4 mL of THF at rt was added 0.36 mL of potassiumbis(trimethylsilyl)amide and the reaction mixture was stirred for 30min. The reaction mixture was cooled to 0° C. and to it was added asolution of 0.04 g (0.089 mmol) of1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidinein 2 mL of THF. The reaction mixture was warmed to rt and stirred for1.2 h. The reaction mixture was filtered through a thin pad of silicaeluting with acetone:hexanes, 1:2, then concentrated. The residue waspurified by chromatography (silica, acetone:hexanes, 1:2) to give thetitle compound. Mass Spectrum (ESI) m/e=444 (M+1).

The following compounds are prepared as described in Examples 1, 37 or47.

EXAMPLE 51

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(ethyl)pyrrolidine

A mixture of 0.023 g (5 mmol) of1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidineand 0.025 g of Pd/C (10%) in 8 mL of CH₃OH was hydrogenated under H₂ (50psi) for 72 h. The reaction mixture was filtered and concentrated togive the title compound. Mass Spectrum (CI) m/e 444 (M+1).

EXAMPLE 52

1-(1-Naphthoyl)-3-(RS)4-(4-fluorophenyl)piperidinylmethyl)-4(SR)-(prop-1-ethyl)pyrrolidine

The title compound was prepared according to procedures described inExample 50. Mass Spectrum (CI) m/e 457 (M+1).

EXAMPLE 53

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2-methylprop-1-enyl)pyrrolidine

The title compound was prepared according to procedures described inExample 50. Mass Spectrum (CI) m/e 471 (M+1).

EXAMPLE 54

1-(8-Quinolinecarbonyl)-3-(RS)4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

The title compound was prepared from3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidineand 8-quinolinecarboxylic acid as described in Example 43. Mass Spectrum(CI) m/e 444 (M+1).

Preparation of3-(RS)4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

Step 1

1-Benzyl-3-(RS)-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(formyl)pyrrolidine

The title compound was prepared from1-benzyl-3-(RS)-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(hydroxymethyl)pyrrolidine(Example 2) according to procedures described in Example 4.

Step 2

1-Benzyl-3-(RS)-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

The title compound was prepared from1-benzyl-3-(RS)-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(formyl)pyrrolidineaccording to procedures described in Example 50.

Step 3

1-(2,2,2-Trichloroethoxycarbonyl)-3-(RS)-(4-Fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

To a solution of 0.625 g (1.4 mmol) of1-benzyl-3-(RS)-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidinein 5 mL of THF at rt was added 0.21 mL (1.55 mmol) of2,2,2-Trichloroethylchloroformate and the reaction mixture was stirredfor 1 h. The reaction mixture was diluted with ether and was washed withsat'd NaHCO₃ and NaCl solutions, dried over Na₂SO₄, filtered and thefiltrate was concentrated. The residue was purified by chromatography(silica, hexanes:EtOAc, 4:1) to give 0.76 g of the title compound.

Step 4

3-(RS)-(4-Fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

A mixture of 0.76 g (1.4 mmol) of 1-(2,2,2-trichloroethoxycarbonyl)-3-(RS)-(4-Fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidineand 0.45 g (7 mol) of Mg in 4 mL of HOAc was heated at 40° C. for 40min. The reaction mixture was filtered through a thin pad of Celite andthe filtrate was concentrated. The residue was dissolved in ether andthe solution was washed with sat'd NaHCO₃ and NaCl solutions, dried overNa₂SO₄, filtered and the filtrate was concentrated to give 0.28 g of thetitle compound.

EXAMPLE 55

1-(7-Indolecarbonyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

The title compound was prepared from3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine(Example 54) and 7-indolecarboxylic acid as described in Example 43.Mass Spectrum (CI) m/e 432 (M+1).

EXAMPLE 56

1-(1-Methyl-7-indolecarbonyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine

The title compound was prepared from1-(7-indolecarbonyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidineaccording to procedures described in Example 43. Mass Spectrum (CI) m/e446 (M+1).

EXAMPLE 57

1-(1-Methyl-7-indolecarbonyl)-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(vinyl)pyrrolidine

Step 1

N-trans-3-(Ethoxycarbonyl)acryloyl-4-(S)-benzyl-2-oxazolidinone

To a solution of 14.4 g (100 mmol) of monoethyl fumarate and 16.7 mL(120 mmol) of triethylamine in 350 mL of THF at 0° C. was added 12.7 g(105 mmol) of pivaloyl chloride. The reaction mixture was allowed towarm to rt and was stirred for 2 h, then was cooled to −78° C.

Meanwhile, to a solution of 18.6 g (105 mmol) of(S)-benzyl-2-oxazolidinone in 200 mL of THF at −78° C. under nitrogen,was added 75 mL of n-butyllithium (1.6M, 120 mmol) and the solution wasstirred for 30 min at −78° C. This was added via cannula to the firstsolution. After addition was complete, the solution was allowed to warmto room temperature for 2 h.

The reaction was quenched by addition of saturated aqueous NH₄Cl and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, dried over MgSO₄, and filtered. The solution wasconcentrated followed by silica gel chromatography (25% ethylacetate/hexane) to afford 21.4 g the title compound; ¹H NMR (CDCl₃)δ8.15 (d, 1H, J=16 Hz), 6.98 (d, 1H, J=16 Hz), 4.65-4.80 (m, 1H),4.10-4.33 (m, 5H), 3.28 (d of d, 1H, J=13.5, 3.2 Hz), 2.81 (d of d, 1H,J=13.3, 9.4 Hz), 1.21-1.35 (m, 3H); Mass spectrum (ESI) m/e=304 (M+1).

Step 2

(S)-N-[(1-Benzyl)-4-(S)-(ethoxycarbonyl)-3-(R)-pyrolidinylcarbonyl]-4-benzyl-2-oxazolidinoneand(S)-N-[(1-Benzyl)-4-(R)-(ethoxycarbonyl)-3-(S)-pyrolidinylcarbonyl]-4-benzyl-2-oxazolidinone

To a solution of 20 g (66 mmol) of N-trans-3-(ethoxycarbonyl)acryloyl-4-(S)-benzyl-2-oxazolidinone (Step 1) in 200 mL of CH₂Cl₂ at 0°C. was added 16.6 g (70 mmol) ofN-methoxymethyl-N-trimethylsilylmethylbenzylamine, and 1 mL (13.4 mmol)of trifluoroacetic acid and the solution was stirred at 0° C. for 2 hunder nitrogen. The solution was poured into sat'd NaHCO₃ solution andthe layers were separated. The aqueous layer was washed with CH₂Cl₂ andthe combined organic fractions were washed with sat'd NaCl solution,dried over MgSO₄, filtered, and the filtrate was concentrated. Theresidue was purified by silica gel chromatography (ethylacetate:hexanes, 1:4) to afford 10.1 g of the title compound(S)-N-[(1-Benzyl)-4-(S)-(ethoxycarbonyl)-3-(R)-pyrrolidinylcarbonyl]-4-benzyl-2-oxazolidinone.¹H NMR (CDCl₃) δ7.18-7.37 (m, 10H), 4.33-4.38 (m, 1H), 4.48-4.44 (m,1H), 3.71 (d, 1H, J=13.1 Hz), 3.61 (d, 1H, J=13.1 Hz), 1.26 (t, 7.1 Hz);Mass spectrum (ESI) m/e=437 (M+1).

Futher elution afforded the title compound(S)-N-[(1-Benzyl)-4-(R)-(ethoxycarbonyl)-3-(S)-pyrrolidinylcarbonyl]-4-benzyl-2-oxazolidinone;¹H NMR (CDCl₃) δ7.22-7.36 (m, 10H), 4.67-4.71 (m, 1H), 4.44-4.48 (m,1H), 3.61 (d, 1H, J=13.1 Hz), 3.67 (d, 1H, J=13.1 Hz), 1.28 (t, 7.1 Hz);Mass spectrum (ESI) m/e=437 (M+1).

Step 3

1-Benzyl-3-(S)-(n-propanethiocarbonyl)-4-(S)-(ethoxycarbonyl)pyrrolidine

To a cooled (−78° C.) solution of 5.7 g (75.0 mmol) of propanethiol in250 mL THF was added 34.4 mL n-butyllithium (1.6M, 55.0 mmol) and thesolution was stirred for 45 min at −78° C. under nitrogen and thenwarmed to −10° C. To the resulting white suspension was added a solutionof 9.6 g (22.0 mmol) of(S)-N-[(1-Benzyl)-4-(R)-(ethoxycarbonyl)-3-(S)-pyrrolidinylcarbonyl]-4-benzyl-2-oxazolidinonein 250 mL THF. The reaction was stirred for 30 min and then removed fromthe bath and allowed to warm to rt over 1 h. The clear solution waspartitioned between 1.5 L of ether and 500 mL of 1M NaOH and the layerswere separated. The aqueous layer was washed with ether and the combinedorganic fractions were washed with sat'd NCl solution, dried over MgSO₄,filtered, and the filtrate was concentrated.

The residue was purified by silica gel chromatography (acetone:hexanes,1:4) to afford 6.6 g of the title compound; Mass spectrum (ESI) m/e=336(M+1).

Step 4

1-Benzyl-3-(S)-(formyl)-4-(S)-(ethoxycarbonyl)pyrrolidine

To a mixture of 0.375 g of 10% Pd/C and 6.5 g (19.4 mmol) of1-benzyl-3-(S)-(n-propanethiocarbonyl)-4-(S)-(ethoxycarbonyl)pyrrolidinein 30 mL acetone was added dropwise 7.5 mL (47.0 mmol) of triethylsilaneover 15 min. The mixture was allowed to stir for 45 min after additionwas complete. The reaction mixture was filtered through a thin pad ofcelite and the filtrate was concentrated. The residue was purified bychromatography (silica, acetone:hexanes, 1:4) to give 4.2 g of titlecompound; ¹H NMR (CDCl₃) δ9.69 (s, 1H), 7.25-7.33 (m, 5H), 4.18 (q, 2H,J=7.1 Hz), 4.44-4.48 (m, 1H), 3.61 (d, 1H, J=13.5 Hz), 3.64 (d, 1H,J=13.5 Hz), 3.32 (m, 1H), 3.46 (m, 1H), 1.27 (t, 7.1 Hz); Mass spectrum(ESI) m/e=262 (M+1).

Step 5

1-Benzyl-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(ethoxycarbonyl)pyrrolidine

To a solution of 4.0 g (15.3 mmol) of1-benzyl-3-(S)-(formyl)-4-(S)-(ethoxycarbonyl)pyrrolidine in 50 mL ofdichloroethane at 0° C. was added 3.3 g (18.4 mmol) of4-fluorophenyl-4-piperidine and the reaction mixture was allowed to stirfor 15 min. To the reaction mixture was added 6.7 g (32.0 mmol) ofsodium triacetoxyborohydride and the solution was stirred for 30 minthen it was warmed to rt. The reaction mixture was quenched with 15 mLsaturated KHCO₃ solution, partitioned between 300 mL of ether and 10 mLof water and the layers were separated. The aqueous layer was washedwith 10 mL of ethyl acetate and the combined organic fractions werewashed with sat'd NaCl solution, dried over MgSO₄, filtered, and thefiltrate was concentrated. The residue was purified by chromatography(silica, acetone:hexanes, 1:4) to afford 5.32 g of the title compound;¹H NMR (CDCl₃) δ7.18-7.33 (m, 7H), 6.95-7.00 (m, 2H), 4.15 (q, 2H, J=7.0Hz), 4.44-4.48 (m, 1H), 3.65 (d, 1H, J=12.6 Hz), 3.56 (d, 1H, J=12.6Hz), 3.40 (m, 1H), 3.03 (m, 2H), 2.45 (m, 2H), 2.07 (m, 2H), 1.6-1.8 (m,4H), 1.23 (t, 7.0 Hz); Mass spectrum (ESI) m/e=425 (M+1).

Step 6

1-Benzyl-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(formyl)pyrrolidine

To a cooled (−65° C.) solution of 2.1 g (50.0 mmol) of1-benzyl-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(ethoxycarbonyl)pyrrolidinein 100 mL toluene was added 43.5 mL of diisobutylaluminum hydride(DIBAL-H) (1.5 M in toluene, 65.0 mmol) dropwise over 30 min and thesolution was stirred for 2 h at −60-65° C. under nitrogen. The reactionwas quenched with 1 mL MeOH and removed from bath and allowed to stir atrt for 10 min. To the solution was added 200 mL of saturated Rochellessalt solution and 100 mL ethyl acetate and the mixture was stirred untilthe solution cleared. The layers were separated and the organic fractionwas washed with sat'd NaCl solution, dried over MgSO₄, filtered, and thefiltrate was concentrated. The residue was purified by chromatography(silica, acetone:hexanes, 1:4) to afford 1.49 g of the title compound;Mass spectrum (ESI) m/e=381 (M+1).

Step 7

1-Benzyl-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(vinyl)pyrrolidine

To a mixture of 1.65 g (4.62 mmol) methyl triphenylphosponium bromide in10 mL THF at −78° C. was added 8.6 mL of potassiumbis(trimethylsilyl)amide (KHMDS, 0.5M in toluene, 4.3 mmol) and thesolution was stirred for 30 min at −78° C. under nitrogen. To thismixture was added a solution of 1.25 g (3.3 mmol) of1-benzyl-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(formyl)pyrrolidine in 5 ml THF. The reaction was warmed to rt over 2 h. Thereaction was partitioned between ethyl acetate and water. The organicfraction was washed with sat'd NaCl solution, dried over MgSO₄,filtered, and the filtrate was concentrated. The residue was purified bychromatography (silica, acetone:hexanes, 1:4) to afford 0.98 g of thetitle compound; Mass spectrum (ESI) m/e=379 (M+1).

Step 8

3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(vinyl)pyrrolidine

To a solution of 0.9 g (2.38 mmol) of1-benzyl-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(vinyl)pyrrolidinein 20 mL THF at at 0° C. was added 0.69 mg (2.65 mmol) of9-fluorenylmethoxycarbonylchloride (FMOC-Cl) and the solution wasstirred for 2 h. The reaction was partitioned between ethyl acetate andsat'd NaHCO₃ solution and the layers were separated. The aqueous layerwas washed with ethyl acetate and the combined organic fractions werewashed with sat'd NaCl solution, dried over MgSO₄, filtered, and thefiltrate was concentrated. The residue was filtered through a pad ofsilica with 30% ethyl acetate/hexane and concentrated. The residue wasdissolved in 5 mL DMF and 1 mL of diethylamine was added and thesolution was stirred for 2 h at rt under nitrogen. An additional 0.5 mLdiethylamine was added and allowed to stir 1 hr. The reaction wasconcentrated and the residue dissolved in dichloromethane and filteredthrough a pad of silica with 30% ethyl acetate/hexane to removeimpurities and then the pad of silica was washed withCHCL₃/MeOH/NH₃(aq)(90:10:1) and concentrated to collect 0.512 g of thetitle compound; Mass spectrum (ESI) m/e=289 (M+1).

Step 9

1-(1-Methyl-7-indolecarbonyl)-3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(vinyl)pyrrolidine

The title compound was prepared from3-(R)-4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(vinyl) pyrrolidine and1-methylindole-7-carboxylic acid (Example 47, Step 3) according toprocedures described in Example 43. The residue was purified bychomatography (HPLC Waters Nova-Pak Silica 25×10 RCM 25-40% acetone inhexanes) to give the title compound. ¹H NMR (CD3OD) δ7.66 (m, 1H),6.98-7.26 (m, 7H), 6.50 (m, 1H), 5.60-5.88 (m, 1H), 5.18-5.38 (m, 2H),4.00-4.34 (m, 1H), 3.80 (m, 3H), 2.55-3.75 (m, 12H), 1.93-2.09 (m, 4H);Mass spectrum (ESI) m/e=446 (M+1). [α]_(D)=−38.8 (c=0.025, CHCl₃).

EXAMPLE 58

1-(7-Indolecarbonyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine

The title compound was prepared from3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine(Example 33, Step 3) and 7-indolecarboxylic acid according to proceduresdescribed in Example 42. Mass Spectrum (CI) m/e 478 (M+1).

EXAMPLE 59

1-(1-Methyl-7-indolecarbonyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine

The title compound was prepared from1-(7-indolecarbonyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidineaccording to procedures described in Example 43. Mass Spectrum (CI) m/e492 (M+1).

EXAMPLE 60

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2-methyl-1,3-dioxolan-2-yl)pyrrolidine

The title compound was prepared from1-(1-naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(acetyl)pyrrolidine(Example 27) according to procedures described in Example 33. MassSpectrum (CI) m/e 503 (M+1).

EXAMPLE 61

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2,2-dimethyl-1,3-dioxolan-5-yl)pyrrolidine

Step 1

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,2-dihydroxyethyl)pyrrolidine

To a solution of 0.023 g (0.05 mmol) of1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(vinyl)pyrrolidine(Example 50) in 1 mL of pyridine, 2 mL of THF and 1 mL of H₂O at rt wasadded 0.016 g (0.06 mmol) of OsO_(4,) and the reaction was stirred for 2h. The reaction mixture was diluted with THF and H2S gas was bubbledthrough it for 5 min. The reaction mixture was filtered through a thinpad of celite and the filtrate was concentrated. The residue waspurified by chromatography (silica, CH₂Cl₂; NH₃ (2N in CH₃OH), 95:5) togive 0.013 g of the title compound.

Step 2

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2,2-dimethyl-1,3-dioxolan-5-yl)pyrrolidine

A solution of 0.013 g (0.027 mmol) of1-(1-naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,2-dihydroxyethyl)pyrrolidine,0.2 mL (1.6 mmol) of 2,2-dimethoxypropane and 0.01 g ofp-toluenesulfonic acid in 2 mL of DMF was stirred at rt for 16 h. Thereaction mixture as concentrated and the residue was dissolved in ether.The ether solution was washed with sat'd NaHCO₃ and sat'd NaClsolutions, dried over MgSO₄, filtered and the filtrate was concentrated.The residue as purified by chromatography (silica, hexanes, EtOAc:NH3(2N in CH₃OH), 10:10:1) to give the two isomers of the title compound.

Isomer #1 Mass Spectrum (CI) m/e 517 (M+1). Isomer #2 Mass Spectrum (CI)m/e 517 (M+1).

EXAMPLE 62

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dithiolan-2-yl)pyrrolidine

A solution of 0.11 g (0.254 mmol) of1-(1-naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(formyl)pyrrolidine,0.043 mL (0.5 mmol) of 1,2-ethanedithiol and 0.042 mL (0.3 mmol) ofBF₃.2HOAc in 4 mL of CH₂Cl₂ was stirred at rt for 2 h. The reactionmixture was diluted with ether and was washed with sat'd NaHCO₃ and NaClsolutions, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chromatography (silica,hexanes:EtOAc:NH₃ (2N in CH₃OH), 20:20:1) to give the title compound.Mass Spectrum (CI) m/e 521 (M+1).

EXAMPLE 63

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(tetrahydrofuran-2-yl)pyrrolidine

Step 1

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-benzyloxy-1-hydroxy-n-but-1-yl)pyrrolidine

A mixture of 1 mL (5.67 mmol) of 3-benzyloxy-1-bromopropane and 0.19 g(7.9 mmol) of Mg in 4 mL of THF was stirred at 65° C. for 1 h. To thisstirred reaction mixture was added a solution of 0.166 g (0.37 mmol) of1-(1-naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(formyl)pyrrolidinein 2 mL of THF and the reaction mixture was stirred at rt for 1 h. Thereaction mixture was diluted with ether and was washed with sat'd NaHCO₃and NaCl solutions, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by chromatography (silica,hexanes:EtOAc:NH₃ (2N in CH₃OH) 10:10:1) to give 0.16 g of the titlecompound.

Step 2

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,4dihydroxy-n-but-1-yl)pyrrolidine

A mixture 0.1 g (0.17 mmol) of-(1-naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-benzyloxy-1-hydroxy-n-but-1-yl)pyrrolidineand 0.12 g of Pd/C (10%) in 8 mL of a 4.4% solution of HCO₂H in CH₃OHwas heated at reflux for 2 h. The reaction mixture was filtered and thefiltrate was concentrated. The residue was dissolved in CH₂Cl₂ and waswashed with sat'd NaHCO₃ solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated. The title compound was used without furtherpurification.

Step 3

1-(1-Naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(tetrahydrofuran-2-yl)pyrrolidine

A solution of 0.018 g (0.036 mmol) of1-(1-naphthoyl)-3-(RS)-4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,4dihydroxy-n-but-1-yl)pyrrolidineand 0.021 g (0.11 mmol) of p-toluenesulfonic acid in 4 mL of benzene washeated at reflux for 2 h. The reaction mixture was diluted with etherand was washed with sat'd NaHCO₃ and NaCl solutions, dried over Na₂SO₄,filtered and the filtrate was concentrated. The residue was purified bychromatography (silica, hexanes:EtOAc:NH₃ (2N in CH₃OH) 10:10:1) to givethe title compound. Mass Spectrum (CI) m/e 487 (M+1).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A compound of the formula I:

wherein: R¹ is —X-R⁸, wherein X is selected from the group consistingof: (1) —CH₂—, (2) —CO—, (3) —CH₂CH₂—, (4) —CH₂CH₂CH₂—, and (5) —CH(C₁₋₆alkyl)-, and wherein R⁸ is a selected from: phenyl, naphthyl, biphenyl,fluorenyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl,octahydronaphthyl, adamantyl, and heterocycle, which may beunsubstituted or substituted, where the substituents are independentlyselected from: (a) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein thealkyl, alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from: (i) hydroxy, (ii) halogen,(iii) —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently selected fromhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl,alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from: (A) phenyl, unsubstitutedor substituted, wherein the substituents are independently selectedfrom: halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), or trifluoromethyl, (B)naphthyl, unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl, (C) heterocycle, unsubstituted or substituted, whereinthe substituents are independently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆ alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)(C₁₋₆ alkyl), or trifluoromethyl, (D) hydroxy, (E) —O(C₁₋₆ alkyl),(F) —CO₂(C₁₋₆ alkyl), (G) —S(O)_(n)—(C₁₋₆ alkyl), wherein n is aninteger selected from 0, 1 and 2, (H) halogen, (I) —NH₂, (J) —NH(C₁₋₆alkyl), and (K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), (iv) —NR⁹-COR¹⁰, (v)—NR⁹-CO₂R¹⁰, (vi) —CO—NR⁹R¹⁰, (vii) —OCO—NR⁹R¹⁰, (viii) —NR⁹CO—NR⁹R¹⁰,(ix) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0, 1 and 2,(x) —NR⁹S(O)₂-R¹⁰, (xi) —NR⁹S(O)₂—NR⁹R¹⁰, (xii) —S(O)_(n)-R⁹, (xiii)—CF₃, (xiv) —CHF₂, (xv) —CH₂F, (xvi) —O-R⁹, (xvii) —O(C₁₋₆ alkyl)-O-R⁹,(xviii) phenyl, (xix) naphthyl, (xx) indenyl, (xxi) indanyl, (xxii)heterocycle, (xxiii) —CO-phenyl, (xxiv) —CO-naphthyl, (xxv) —CO-indenyl,(xxvi) —CO-indanyl, (xxvii) —CO-heterocycle, (xxviii) —OCO-R⁹, (xxix)—OCO₂-R⁹, and (xxx) —CO-R⁹, (b) —O-C₁₋₆ alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆alkynyl, wherein the alkyl, alkenyl, or alkynyl is unsubstituted orsubstituted, wherein the substituents are independently selected from:(i) hydroxy, (ii) halogen, (iii) —NR⁹R¹⁰, (iv) —NR⁹-COR¹⁰, (v)—NR⁹-CO₂R¹⁰, (vi) —CO—NR⁹R¹⁰, (vii) —OCO—NR⁹R¹⁰, (viii) —NR⁹CO—NR⁹R¹⁰,(ix) —S(O)₂—NR⁹R¹⁰, (x) —NR⁹S(O)₂-R¹⁰, (xi) —NR⁹S(O)₂—NR⁹R¹⁰, (xii)—S(O)_(n)-R⁹, (Xiii) —CF₃, (xiv) —CHF₂, (xv) —CH₂F, (xvii) —O-R⁹, (xvii)—O(C₁₋₆ alkyl)-O-R⁹, (xviii) phenyl, (xix) naphthyl, (xx) indenyl, (xxi)indanyl, (xxii) heterocycle, (xxiii) —CO-phenyl, (xxiv) —CO-naphthyl,(xxv) —CO-indenyl, (xxvi) —CO-indanyl, (xxvii) —CO-heterocycle, (xxviii)—OCO-R⁹, (xxix) —OCO₂-R⁹, and (xxx) —CO-R⁹, (c) —NO₂, (d) hydroxy, (e)halogen, (f) —NR⁹R¹⁰, (g) —NR⁹-COR¹⁰, (h) —NR⁹-CO₂R₁₀, (i) —CO—NR⁹R¹⁰,(j) —OCO—NR⁹R¹⁰, (k) —NR⁹CO—NR⁹R¹⁰, (l) —S(O)₂—NR⁹R¹⁰, (m)—NR⁹S(O)₂-R¹⁰, (n) —NR⁹S(O)₂—NR⁹R¹⁰, (o) —S(O)_(n)-R⁹, (p) —CF₃, (q)—CHF₂, (r) —CH₂F, (s) —OCO-R⁹, (t) —OCO₂-R⁹, and (u) —CO-R⁹; R² isselected from the group consisting of:

 wherein R⁵ is a selected from: (1) —NR⁶CO—O-R⁷, wherein R⁶ is hydrogen,C₁₋₆ alkyl or C₁₋₆ alkyl-C₅₋₆ cycloalkyl, and R⁷ is C₁₋₆ alkyl, C₅₋₆cycloalkyl, benzyl or phenyl, wherein the alkyl, cycloalkyl, benzyl orphenyl is unsubstituted or substituted with halogen, C₁₋₃ alkyl, C₁₋₃alkoxy or trifluoromethyl, (2) phenyl, which is unsubstituted orsubstituted with halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl, (3) -pyridyl, (4)-thienyl, (5) -C₁₋₆ alkyl-phenyl, -C₁₋₆ alkyl-naphthyl, -C₁₋₆alkyl-indenyl, -C₁₋₆ alkyl-indanyl, and -C₁₋₆ alkyl-heterocycle, whereinthe phenyl, naphthyl, indenyl, indanyl, or heterocycle is unsubstitutedor substituted with: halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl; and whereinthe -C₁₋₆ alkyl is optionally substituted with oxo, hydroxy, C₁₋₆alkoxy, acetoxy, or halogen, (6) —O-C₁₋₆ alkyl-phenyl, —O-C₁₋₆alkyl-naphthyl, —O-C₁₋₆ alkyl-indenyl, —O-C₁₋₆ alkyl-indanyl, and—O-C₁₋₆ alkyl-heterocycle, wherein the phenyl, naphthyl, indenyl,indanyl, or heterocycle is unsubstituted or substituted with: halogen,hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹,—NR⁹R¹⁰, or trifluoromethyl, (7) C₁₋₄ alkyl-O-C-₁₋₄ alkyl-phenyl,wherein the phenyl is unsubstituted or substituted with halogen,hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹,—NR⁹R¹⁰, or trifluoromethyl, and (8) -C₁₋₄ alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein the phenyl is unsubstituted or substituted withhalogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂,—NHR⁹, —NR⁹R¹⁰, or trifluoromethyl; and wherein R¹¹ is a selected from:(1) -hydrogen, (2) —OH, (3) -C₁₋₆ alkyl, and (4) -halogen; R³ isselected from the group consisting of: (1) —CHO, (2) —CO₂(C₁₋₆ alkyl),(3) —CO-R⁹, (4) —CONR⁹R¹⁰, (5) —CONR⁹-COR¹⁰, (6) —CONR⁹-CO₂R¹⁰, (7)—C(R⁹)(OR⁹)(OR¹⁰), (8) —C(R⁹)(SR⁹)(SR¹⁰), (9) —C(R⁹)(OR¹⁴)(OR¹⁵),wherein R¹⁴ and R¹⁵ are joined together in a C₂₋₃ alkyl group to form a5- or 6-membered ring which is substituted with R¹² and R¹³ wherein: R¹²and R¹³ are independently selected from: (a) hydrogen, (b) —CO₂(C₁₋₆alkyl), (c) hydroxy, (d) halogen, (e) —NR⁹R¹⁰, (f) —NR⁹-COR¹⁰, (g)—NR⁹-CO₂R¹⁰, (h) —CF₃, (i) —CHF₂, (j) —CH₂F, (k) —O-R⁹, (l) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl, or alkynyl isunsubstituted or substituted, wherein the substituents are independentlyselected from: (i) —CO₂(C₁₋₆ alkyl), (ii) hydroxy, (iii) halogen, (iv)—NR⁹R¹⁰, (v) —NR⁹-COR¹⁰, (vi) —NR⁹-CO₂R¹⁰, (vii) phenyl, (viii) —CF₃,(ix) —CHF₂, (x) —CH₂F, and (xi) —O-R⁹, (m) phenyl or heterocycle,wherein the phenyl or heterocycle is unsubstituted or substituted,wherein the substituents are independently selected from: (i) —CO₂(C₁₋₆alkyl), (ii) hydroxy, (iii) halogen, (iv) —NR⁹R¹⁰, (v) —NR⁹-COR¹⁰, (vi)—NR⁹-CO₂R¹⁰, (vii) phenyl, (viii) —CF₃, (ix) —CHF₂, (x) —CH₂F, and (xi)—O-R⁹, (10) —C(R⁹)(SR¹⁴)(SR¹⁵), (11) -cyclopentyl, which is substitutedwith R¹² and R¹³, (12) -cyclohexyl, which is substituted with R¹² andR¹³, (13) -tetrahydrofuranyl, which is substituted with R¹² and R¹³,(14) -tetrahydropyranyl, which is substituted with R¹² and R¹³; R^(4c),R_(4d), and R^(4f) are independently selected from the group consistingof: (1) hydrogen, and (2) C₁₋₆ alkyl; and pharmaceutically acceptablesalts thereof and individual diastereomers thereof.
 2. A compound of theformula Ib:

wherein: R¹ is —X-R⁸, wherein X is selected from the group consistingof: (1) —CH₂—, (2) —CO—, and (3) —CH₂CH₂—, and wherein R⁸ is a selectedfrom: phenyl, naphthyl, biphenyl, fluorenyl, indenyl, indanyl,dihydronaphthyl, tetrahydronaphthyl, octahydronaphthyl, adamantyl, andheterocycle, which may be unsubstituted or substituted, where thesubstituents are independently selected from: (a) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl, or alkynyl isunsubstituted or substituted, wherein the substituents are independentlyselected from: (i) hydroxy, (ii) halogen, (iii) —NR⁹R¹⁰, wherein R⁹ andR¹⁰ are independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein the alkyl, alkenyl, or alkynyl isunsubstituted or substituted, wherein the substituents are independentlyselected from: (A) phenyl, unsubstituted or substituted, wherein thesubstituents are independently selected from: halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)(C₁₋₆ alkyl), or trifluoromethyl, (B) naphthyl, unsubstituted orsubstituted, wherein the substituents are independently selected from:halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), or trifluoromethyl, (C)heterocycle,unsubstituted or substituted, wherein the substituents areindependently selected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,—CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl, (D) hydroxy, (E) —O(C₁₋₆ alkyl), (F) —CO₂(C₁₋₆ alkyl),(G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is an integer selected from 0, 1and 2, (H) halogen, (I) —NH₂, (J) —NH(C₁₋₆ alkyl), and (K) —N(C₁₋₆alkyl)(C₁₋₆ alkyl), (iv) —NR⁹-COR¹⁰, (v) —NR⁹-CO₂R¹⁰, (vi) —CO—NR⁹R¹⁰,(vii) —OCO—NR⁹R¹⁰, (viii) —NR⁹CO—NR⁹R¹⁰, (ix) —S(O)₂—NR⁹R¹⁰, wherein nis an integer selected from 0, 1 and 2, (x) —NR⁹S(O)₂-R¹⁰, (xi)—NR⁹S(O)₂—NR⁹R¹⁰, (xii) —S(O)_(n)-R⁹, (xiii) —CF₃, (xiv) —CHF₂, (xv)—CH₂F, (xvi) —O-R⁹, (xvii) —O(C₁₋₆ alkyl) —O-R⁹, (xviii) phenyl, (xix)naphthyl, (xx) indenyl, (xxi) indanyl, (xxii) heterocycle, (xxiii)—CO-phenyl, (xxiv) —CO-naphthyl, (xxv) —CO-indenyl, (xxvi) —CO-indanyl,(xxvii) —CO-heterocycle, (xxviii) —OCO-R⁹, (xxix) —OCO₂-R⁹, and (xxx)—CO-R⁹, (b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆ alkynyl, wherein thealkyl, alkenyl, or alkynyl is unsubstituted or substituted, wherein thesubstituents are independently selected from: (i) hydroxy, (ii) halogen,(iii) —NR⁹R¹⁰, (iv) —NR⁹-COR¹⁰, (v) —NR⁹-CO₂R¹⁰, (vi) —CO—NR⁹R¹⁰, (vii)—OCO—NR⁹R¹⁰, (viii) —NR⁹CO—NR⁹R¹⁰, (ix) —S(O)₂—NR⁹R¹⁰, (x)—NR⁹S(O)₂-R¹⁰, (xi) —NR⁹S(O)₂—NR⁹R¹⁰, (xii) —S(O)_(n)-R⁹, (xiii) —CF₃,(xiv) —CHF₂, (xv) —CH₂F, (xvii) —O-R⁹, (xvii) —O(C₁₋₆ alkyl)-O-R⁹,(xviii) phenyl, (xix) naphthyl, (xx) indenyl, (xxi) indanyl, (xxii)heterocycle, (xxiii) —CO-phenyl, (xxiv) —CO-naphthyl, (xxv) —CO-indenyl,(xxvi) —CO-indanyl, i(xxvii) —CO-heterocycle, (xxviii) —OCO-R⁹, (xxix)—OCO₂-R⁹, and (xxx) —CO-R⁹, (c) —NO₂, (d) hydroxy, (e) halogen, (f)—NR⁹R¹⁰, (g) —NR⁹-COR¹⁰, (h) —NR⁹-CO₂R¹⁰, (i) —CO—NR⁹R¹⁰, (j)—OCO—NR⁹R¹⁰, (k) —NR⁹CO—NR⁹R¹⁰, (l) —S(O)₂—NR⁹R¹⁰, (m) —NR⁹S(O)₂-R¹⁰,(n) —NR⁹S (O)₂—NR⁹R¹⁰, (o) —S(O)_(n)-R⁹, (p) —CF₃, (q) —CHF₂, (r) —CH₂F,(s) —OCO-R⁹, (t) —CO₂-R⁹, and (u) —COR⁹; R² is:

 wherein R⁵ is a selected from: (1) —NR⁶CO—O-R⁷, wherein R⁶ is hydrogen,C₁₋₆ alkyl or C₁₋₆ alkyl-C₅₋₆ cycloalkyl, and R⁷ is C₁₋₆ alkyl, C₅₋₆cycloalkyl, benzyl or phenyl, wherein the alkyl, cycloalkyl, benzyl orphenyl is unsubstituted or substituted with halogen, C₁₋₃alkyl,C₁₋₃alkoxy or trifluoromethyl, (2) phenyl, which is unsubstituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl, (3) -pyridyl, (4)-thienyl, (5) -C₁₋₆alkyl-phenyl, -C₁₋₆alkyl-naphthyl,-C₁₋₆alkyl-indenyl, -C₁₋₆alkyl-indanyl, and -C₁₋₆alkyl-heterocycle,wherein the phenyl, naphthyl, indenyl, indanyl, or heterocycle isunsubsituted or substituted with: halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl;and wherein the -C₁₋₆alkyl is optionally substituted with oxo, hydroxy,C₁₋₆alkoxy, acetoxy, or halogen, (6) —O-C₁₋₆alkyl-phenyl,—O-C₁₋₆alkyl-naphthyl, —O-C₁₋₆alkyl-indenyl, —O-C₁₋₆alkyl-indanyl, and—O-C₁₆alkyl-heterocycle, wherein the phenyl, naphthyl, indenyl, indanyl,or heterocycle is unsubsituted or substituted with: halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, -CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, ortrifluoromethyl, (7) -C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein the phenylis unsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl,and (8) -C₁₋₄alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl;and wherein R¹¹ is a selected from: (1) -hydrogen, (2) —OH, (3)-C₁₋₆alkyl, and (4) -halogen; R¹² and R¹³ are independently selectedfrom: (1) hydrogen, (2) —CO₂(C₁₋₆ alkyl), (3) hydroxy, (4) halogen, (5)—NR⁹R¹⁰, (6) —NR⁹-COR¹⁰, (7) —NR⁹-CO₂R¹⁰, (8) —CF₃, (9) —CHF₂, (10)—CH₂F, (11) —O-R⁹, (12) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, whereinthe alkyl, alkenyl, or alkynyl is unsubstituted or substituted, whereinthe substituents are independently selected from: (a) —CO₂(C₁₋₆ alkyl),(b) hydroxy, (c) halogen, (d) —NR⁹R¹⁰, (e) —NR⁹-COR¹⁰, (f) —NR⁹-CO₂R¹⁰,(g) phenyl, (h) —CF₃, (i) —CHF₂, () —CH₂F, and (k) —O-R⁹, (14) phenyl orheterocycle, wherein the phenyl or heterocycle is unsubstituted orsubstituted, wherein the substituents are independently selected from:(a) —CO₂(C₁₋₆ alkyl), (b) hydroxy, (c) halogen, (d) —NR⁹R¹⁰, (e)—NR⁹-COR¹⁰, (f) —NR⁹-CO₂R¹⁰, (g) phenyl, (h) —CF₃, (i) —CHF₂, (j) —CH₂F,and (k) —O-R⁹, Y and Z are independently selected from: C₁ alkyl, —O—,—S(O)_(n)— and —N(R⁹); m is an integer selected from 1 and 2; andpharmaceutically acceptable salts thereof and individual diastereomersthereof.
 3. The compound of claim 2 of the formula Id:

wherein: R is —X-R⁸, wherein X is selected from the group consisting of:(1) —CH₂—, and (2) —CO—, and wherein R⁸ is a selected from: phenyl,naphthyl, indenyl, indanyl, indolyl, quinolyl, isoquinolyl,benzofuranyl, dihydrobenzofuranyl, methylenedioxybenzoyl,benzopyrazolyl, and benzotriazolyl, which may be unsubstituted orsubstituted, where the substituents are independently selected from: (a)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl, oralkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from: (i) hydroxy, (ii) halogen, (iii) —NR⁹R¹⁰,wherein R⁹ and R¹⁰ are independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the alkyl, alkenyl, or alkynylis unsubstituted or substituted, wherein the substituents areindependently selected from: (A) phenyl, unsubstituted or substituted,wherein the substituents are independently selected from: halogen,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)(C₁₋₆ alkyl), or trifluoromethyl, (B) naphthyl,unsubstituted or substituted, wherein the substituents are independentlyselected from: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), ortrifluoromethyl, (C) heterocycle,unsubstituted or substituted, whereinthe substituents are independently selected from: halogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)(C₁₋₆ alkyl), or trifluoromethyl, (D) hydroxy, (E) —O(C₁₋₆ alkyl),(F) —CO₂(C₁₋₆ alkyl), (G) —S(O)_(n)-(C₁₋₆ alkyl), wherein n is aninteger selected from 0, 1 and 2, (H) halogen, (I) —NH₂, (J) —NH(C₁₋₆alkyl), and (K) —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), (iv) —NR⁹-COR¹⁰, (v)—NR⁹-CO₂R¹⁰, (vi) —CO—NR⁹R¹⁰, (vii) —OCO—NR⁹R¹⁰, (viii) —NR⁹CO—NR⁹R¹⁰,(ix) —S(O)₂—NR⁹R¹⁰, wherein n is an integer selected from 0,1 and2, (x)—NR⁹S(O)₂-R¹⁰, (xi) —NR⁹S(O)₂—NR⁹R¹⁰, (xii) —S(O)_(n)-R⁹, (xiii) —CF₃,(xiv) —CHF₂, (xv) —CH₂F, (xvi) —O-R⁹, (xvii) —O(C₁₋₆ alkyl) —O-R⁹,(xviii) phenyl, (xix) naphthyl, (xx) indenyl, (xxi) indanyl, (xxii)heterocycle, (xxiii) —CO-phenyl, (xxiv) —CO-naphthyl, (xxv) —CO-indenyl,(xxvi) —CO-indanyl, (xxvii) —CO-heterocycle, (xxviii) —OCO-R⁹, (xxix)—OCO₂-R⁹, and (xxx) —CO-R⁹, (b) —O-C₁₋₆alkyl, —O-C₂₋₆ alkenyl, —O-C₂₋₆alkynyl, wherein the alkyl, alkenyl, or alkynyl is unsubstituted orsubstituted, wherein the substituents are independently selected from:(i) hydroxy, (ii) halogen, (iii) —NR⁹R¹⁰, (iv) —NR⁹-COR¹⁰, (v)—NR⁹-CO₂R¹⁰, (vi) —CO—NR⁹R¹⁰, (vii) —OCO—NR⁹R¹⁰, (viii) —NR⁹CO—NR⁹R¹⁰,(ix) —S(O)₂—NR⁹R¹¹, (x) —NR⁹S(O)₂-R¹⁰, (xi) —NR⁹S(O)₂—NR⁹R¹⁰, (xii)—S(O)_(n)-R⁹, (xiii) —CF₃, (xiv) —CHF₂, (xv) —CH₂F, (xvii) —O-R⁹, (xvii)—O(C₁₋₆ alkyl)-O-R⁹, (xviii) phenyl, (xix) naphthyl, (xx) indenyl, (xxi)indanyl, (xxii) heterocycle, (xxiii) —CO-phenyl, (xxiv) —CO-naphthyl,(xxv) —CO-indenyl, (xxvi) —CO-indanyl, (xxvii) —CO-heterocycle, (xxviii)—OCO-R⁹, (xxix) —OCO₂-R⁹, and (xxx) —CO-R⁹, (c) —NO₂, (d) hydroxy, (e)halogen, (f) —NR⁹R¹⁰, (g) —NR⁹-COR¹⁰, (h) —NR⁹-CO₂R¹⁰, (i) —CO—NR⁹R¹⁰,(j) —OCO—NR⁹R¹⁰, (k) —NR⁹CO—NR⁹R¹⁰, (l) —S(O)₂—NR⁹R¹⁰, (m)—NR⁹S(O)₂-R¹⁰, (n) —NR⁹S(O)₂—NR⁹R¹⁰, (o) —S(O)_(n)-R⁹, (p) —CF₃, (q)—CHF₂, (r) —CH₂F, (S) —OCO-R⁹, (t) —OCO₂-R⁹, and (u) —CO-R⁹; wherein R⁵is a selected from: (1) phenyl, which is unsubstituted or substitutedwith halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂,—NHR⁹, —NR⁹R¹⁰, or trifluoromethyl, (2)-C₁₋₆alkyl-phenyl,-C₁₋₆alkyl-naphthyl, -C₁₋₆alkyl-indenyl,-C₁₋₆alkyl-indanyl, and -C₁₋₆alkyl-heterocycle, wherein the phenyl,naphthyl, indenyl, indanyl, or heterocycle is unsubsituted orsubstituted with: halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl; and wherein the-C₁₋₆alkyl is optionally substituted with oxo, hydroxy, C₁₋₆alkoxy,acetoxy, or halogen, (3) —O-C₁₋₆alkyl-phenyl, —O-C₁₋₆alkyl-naphthyl,—O-C₁₋₆alkyl-indenyl, —O-C₁₋₆alkyl-indanyl, and—O-C₁₋₆alkyl-heterocycle, wherein the phenyl, naphthyl, indenyl,indanyl, or heterocycle is unsubsituted or substituted with: halogen,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰,or trifluoromethyl, (4) -C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein thephenyl is unsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl,and (5) -C₁₋₄alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, —CO₂(C₁₋₆ alkyl), —NH₂, —NHR⁹, —NR⁹R¹⁰, or trifluoromethyl;R¹² and R¹³ are independently selected from: (1) hydrogen, (2) —CO₂(C₁₋₆alkyl), (3) hydroxy, (4) halogen, (5) —NR⁹R¹⁰, (6) —NR⁹-COR¹⁰, (7)—NR⁹-CO₂R¹⁰, (8) —CF₃, (9) —CHF₂, (10) —CH₂F, (11) —O-R⁹, (12) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, wherein the alkyl, alkenyl, oralkynyl is unsubstituted or substituted, wherein the substituents areindependently selected from: (a) —CO₂(C₁₋₆ alkyl), (b) hydroxy, (c)halogen, (d) —NR⁹R¹⁰, (e) —NR⁹-COR¹⁰, (f) —NR⁹-CO₂R¹⁰, (g) phenyl, (h)—CF₃, (i) —CHF₂, (j) —CH₂F, and (k) —O-R⁹, (14) phenyl or heterocycle,wherein the phenyl or heterocycle is unsubstituted or substituted,wherein the substituents are independently selected from: (a) —CO₂(C₁₋₆alkyl), (b) hydroxy, (c) halogen, (d) —NR⁹R¹⁰, (e) —NR⁹-COR¹⁰, (f)—NR⁹-CO₂R¹⁰, (g) phenyl, (h) —CF₃, (i) —CHF₂, (j) —CH₂F, and (k) —O-R⁹,Y and Z are independently selected from: C₁ alkyl, —O—, —S(O)_(n)— and—N(R⁹)-; m is an integer selected from 1 and 2; and pharmaceuticallyacceptable salts and individual diastereomers thereof.
 4. The compoundof claim 1 wherein: R¹ is selected from the group consisting of: (1)—CH₂-phenyl, (2) —CO-phenyl, (3) —CH₂-(2,4-dichlorophenyl), (4)—CO-(2,4-dichlorophenyl), (5) —CH₂-(2-naphthyl), (6) —CO-(1-naphthyl),(7) —CH₂-indolyl, and (8) —CO-indolyl.
 5. The compound of claim 1wherein: R¹ is selected from the group consisting of: (1) —CH₂-phenyl,(2) —CO-phenyl, (3) —CH₂-(2,4-dichlorophenyl), (4) —CH₂-(7-indolyl), and(5) —CO-(7-indolyl).
 6. The compound of claim 1 wherein: R² is:

 wherein R⁵ is selected from: (1) phenyl, which is unsubstituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl, (2) -C₁₋₆alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with: halogen; hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, or trifluoromethyl; and wherein the -C₁₋₆alkyl is optionallysubstituted with oxo, hydroxy, C₁₋₆alkoxy, acetoxy, or halogen, (3)—O-C₁₋₆alkyl-phenyl, wherein the phenyl is unsubsituted or substitutedwith halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, or trifluoromethyl, (4)-C₁₋₄alkyl-O-C₁₋₄alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl, and (5) -C₁₋₄alkyl-S(O)_(n)-C₁₋₄alkyl-phenyl, wherein nis an integer selected from 0, 1 and 2, and wherein the phenyl isunsubsituted or substituted with halogen, hydroxy, C₁₋₆alkyl,C₁₋₆alkoxy, or trifluoromethyl.
 7. The compound of claim 1 wherein: R²is:

 wherein R⁵ is a selected from: (1) phenyl, which is unsubstituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl, (2) -C₂₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with chloro, fluoro, trifluoromethyl, methylor ethyl and wherein the -C₂₋₄alkyl is optionally substituted with oxo,hydroxy, halogen, or methoxy, (3) -C₁₋₃alkyl-O-C₁₋₃alkyl-phenyl, whereinthe phenyl is unsubsituted or substituted with chloro, fluoro,trifluoromethyl, methyl or ethyl, and (4)-C₁₋₃alkyl-S(O)_(n)-C₁₋₃alkyl-phenyl, wherein the phenyl is unsubsitutedor substituted with chloro, fluoro, trifluoromethyl, methyl or ethyl. 8.The compound of claim 1 wherein: R² is:

 wherein R⁵ is a selected from: (1) phenyl, which is unsubstituted orsubstituted with halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, ortrifluoromethyl, (2) -C₃₋₄alkyl-phenyl, wherein the phenyl isunsubsituted or substituted with chloro, fluoro or methyl, and whereinthe -C₃₋₄alkyl is optionally substituted with oxo, hydroxy, or methoxy,(3) -C₁₋₃alkyl-O-C₁₋₃alkyl-phenyl, wherein the phenyl is unsubsituted orsubstituted with chloro, fluoro or methyl, and (4)-C₁₋₃alkyl-S(O)_(n)-C₁₋₃alkyl-phenyl, wherein the phenyl is unsubsitutedor substituted with chloro, fluoro or methyl.
 9. The compound of claim 1wherein: R² is:


10. The compound of claim 1 wherein: R³ is selected from the groupconsisting of: (1) —CHO, (2) —CO-R¹⁶, wherein R¹⁶ is C₁₋₆ alkyl, whereinthe alkyl is unsubstituted or substituted, wherein the substituents areindependently selected from: (a) —CO₂(C₁₋₆ alkyl), (b) hydroxy, (c)—O-C₁₋₆ alkyl, (d) halogen, and (e) phenyl, (3) —CO₂-R¹⁶, (4) —CONH₂,(5) —CONR¹⁶R¹⁷, wherein R¹⁷ is hydrogen or is independently selectedfrom the definitions of R¹⁶; (6) —CONH—COR¹⁶, (7) —C(R¹⁷)(OR¹⁶)(OR¹⁶),(8) —C(R¹⁷)(SR¹⁶)(SR¹⁶), (9) —C(R¹⁷)(OR¹⁴)(OR¹⁵), wherein R¹⁴ and R¹⁵are joined together in a C₂₋₃ alkyl group to form a 5- or 6-memberedring which is substituted with R¹² and R¹³ wherein: R¹² and R¹³ areindependently selected from: (a) hydrogen, (b) —CO₂R¹⁶, (c) hydroxy, (d)halogen, (e) —CF₃, (f) —CHF₂, (g) —CH₂F, (h) C₁₋₆ alkyl, wherein thealkyl is unsubstituted or substituted, wherein the substituents areindependently selected from: (i) —CO₂(C₁₋₆ alkyl), (ii) hydroxy, (iii)—O-C₁₋₆ alkyl, (iv) halogen, and (v) phenyl, (i) phenyl, unsubstitutedor substituted, wherein the substituents are independently selectedfrom: (i) C₁₋₆ alkyl, (ii) —CO₂(C₁₋₆ alkyl), (iii) hydroxy, (iv) —O-C₁₋₆alkyl, and (v) halogen, (10) —C(R¹⁷)(SR¹⁴)(SR¹⁵), (11) -cyclopentyl,which is substituted with R¹² and R¹³, (12) -cyclohexyl, which issubstituted with R¹² and R¹³, (13) -tetrahydrofuranyl, which issubstituted with R¹² and R¹³, (14) -tetrahydropyranyl, which issubstituted with R¹² and R¹³.
 11. The compound of claim 1 wherein: R³ isselected from: (1) —CH(OR¹⁴)(OR¹⁵), wherein R¹⁴ and R¹⁵ are joinedtogether in a C₂₋₃ alkyl group to form a 5- or 6-membered ring which issubstituted with R¹² and R¹³ wherein: R¹² and R¹³ are independentlyselected from: (a) hydrogen, (b) C₁₋₆ alkyl, wherein the alkyl isunsubstituted or substituted, wherein the substituents are independentlyselected from: (i) —O-C₁₋₆ alkyl, (ii) halogen, and (iii) phenyl, (c)phenyl, unsubstituted or substituted, wherein the substituents areindependently selected from: (i) C₁₋₆ alkyl, (ii) —O-C₁₋₆ alkyl, (iii)halogen, and (2) —CH(SR¹⁴)(SR¹⁵), (3) -tetrahydrofuranyl, which issubstituted with R¹² and R¹³, (4) -tetrahydropyranyl, which issubstituted with R¹² and R¹³.
 12. The compound of claim 1 wherein:R^(4c), and R^(4h) are each hydrogen and R^(4d) is selected from thegroup consisting of hydrogen, and —CH₃.
 13. The compound of claim 1which is of the stereochemical configuration:


14. A compound which is selected from the group consisting of:1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine;1-Benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(RS)-(ethoxycarbonyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-methoxycarbonylpyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-ethoxycarbonylpyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-isopropyloxycarbonylpyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-benzyloxycarbonylpyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N-ethylaminocarbonyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(N,N-diethylaminocarbonyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-acetylpyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-benzoylpyrrolidine;1-(-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4(SR)-(cyclopentyl)pyrrolidine;1-(1-Methyl-7-indolecarbonoyl)-3-(RS)-((4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclopentyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(cyclohexyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dithiolan-2-yl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2-tetrahydrofuranyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dithian-2-yl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2-tetrahydropyranyl)pyrrolidine;1-(1-Methyl-7-indolecarbonoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dithiolan-2-yl)pyrrolidine;1-(1-Methyl-7-indolecarbonoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(2-tetrahydrofuranyl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine;1-(Benzyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylcarbonyl)-4-(SR)-(1,3-dioxolan-2-yl)pyrrolidine;1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-methyl-1,3-dioxolan-2-yl)pyrrolidine;1-(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-flouromethyl-1,3-dioxolan-2-yl)pyrrolidine;1(2-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(4-methoxymethyl-1,3-dioxolan-2-yl)pyrrolidine;1-(1-Naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-(1,3-dioxan-2-yl)pyrrolidine;and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.
 15. A pharmaceutical composition which comprisesan inert carrier and a compound of claim
 1. 16. A method for treating adisease or condition which requires inhibition of chemokine receptorfunction comprising the administration of a therapeutically effectiveamount of a compound of claim 1.